The Risks and Benefits of Hormone Replacement Therapy—Weighing the Evidence

93 The Risks and Benefits of Hormone Replacement Therapy Weighing the Evidence P H Y L L I S A. W I N G O * AND A N N E M c T I E R N A N t *American Cancer Society, Atlanta, Georgia; tFred Hutchinson Cancer Research Center, Seattle, Washington

similar percentages of physician office visits for treatment of menopausal symptoms resulted in oral estrogen prescriptions (37%) and injected estrogens (36%) [4]. However, by 1986, the mix of oral and injected estrogens had changed to 52 and 14%, respectively [4]. In 1986, transdermal estradiol was first marketed under the brand name Estraderm. Between 1987 and 1992, the number of prescriptions for Estraderm increased threefold from 1.5 to 4.7 million [2]. In Britain, subdermal implant systems for delivering postmenopausal hormones have been available since the 1980s [5]. Similar delivery systems are not approved for use in the United States [Lisa Rarick, Food and Drug Administration, personal communication, September 1998]. Although conjugated estrogens have been available in the United States since the 1940s, they were not widely used until the 1960s [3]. In general, the use of noncontraceptive estrogens has waxed and waned depending on the perceptions of risks and benefits [2,4,6]. During the 1960s and 1970s, estrogen use increased to about 28 million prescriptions in 1975 [6] when several studies reported an association with endometrial cancer (Fig. 93.1) [7,8]. Over the next several years, prescriptions for

I. Introduction

In 1997, an estimated 45.1 million prescriptions for Premarin were dispensed, more than for any other prescription drug in the United States [1]. On average, about one in five menopausal women in the United States were using noncontraceptive hormones in 1992 [2], and an estimated 71% of women who had had a bilateral oophorectomy during 1990-1992 reported having used hormone replacement therapy (HRT) at some time [3]. Because so many peri- and postmenopausal women use hormones for relief of vasomotor symptoms and to treat urogenital atrophy, the balance of health risks and benefits related to this common exposure needs careful consideration.

II. Historic Evolution and Trends in Use

HRT has been available since the 1940s [3], although the specific hormone combinations and delivery systems have changed over time. The earliest approved hormones were administered in oral pills, by injection, and in vaginal creams or suppositories; all of these routes of administration are still in use. In 1974,

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Fig. 93.1 Estimated number of prescriptions dispensed for noncontraceptive estrogen and progestins, 1966-1992. Women and Health

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Copyright 9 2000 by Academic Press. All fights of reproduction in any form reserved.

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noncontraceptive estrogens decreased by half [4,6]. Then, in the early 1980s, use began to increase again, and by 1992, the annual number of prescriptions dispensed for oral menopausal estrogens had increased to previously high levels of 31.7 million [2]. This increase in the use of estrogens in the 1980s actually reflected an increase in the use of combination HRT--estrogen plus progestin therapy. The addition of progestin to estrogen for treating symptoms of menopause ameliorates most of the adverse effects of unopposed estrogen on the uterus [9,10]. III. Characteristics of Women Who Use HRT Because women who use HRT visit their physician regularly to get their hormone prescriptions refilled and to have checkups, they may get an earlier diagnosis and receive treatment for cancer or heart disease [11]. Such differences are important and need to be considered when evaluating the HRT literature. The protective effects of HRT use on cardiovascular disease and perhaps colon cancer and the possible adverse effects on other cancers may be influenced by selection, surveillance, diagnostic, and other biases. Women who use HRT have different sociodemographic characteristics, may be more likely to practice healthy behaviors, and may have a better cardiovascular risk factor profile than women who have never used HRT [3,11-13]. The Epidemiologic Followup Study to the First National Health and Nutrition Examination Survey was used to examine patterns of HRT over time and to describe the characteristics of menopausal women who had ever used this treatment and who continued to use it for at least five years [3]. In this study, women who had ever used HRT were more likely to have undergone hysterectomy or bilateral oophorectomy, to be white, to live in the western United States, to have taken oral contraceptives in the past, to be lean, and to consume more alcohol than women who had never used HRT. Smoking, physical activity, and self-reported health status were not related to HRT use in this cohort. Similarly, serum cholesterol and health conditions such as a history of diabetes mellitus or hypertension were not related to the use of HRT. Other studies described the relationship between HRT use and several of the same factors, including surgical menopause, leanness, and white race [ 11-13 ]. A study of upper-middle class menopausal women ages 50 to 79 years in California examined the relationship between hormone use and healthy changes in lifestyle (e.g., decreased salt and fat intake, increased fiber intake, increased levels of exercise, weight loss, stress reduction, etc.) [ 11 ]. Study participants were asked about physician office visits that resulted in blood pressure checks, cholesterol measurement, screening examinations for cancer, and other prevention activities. All healthy behaviors examined, except for decreased fat and salt intake and use of blood pressure screening, were related to estrogen use. Current estrogen users had the highest prevalence of healthy behaviors, followed by past users and never users. A prospective investigation found a more favorable profile of cardiovascular risk factors before using estrogen replacement therapy among women who subsequently used hormones than among those who did not [ 12]. Prior to using estrogen replacement therapy, women who subsequently used it had higher levels of HDL cholesterol, higher levels of physical activity and

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alcohol consumption, and lower levels of apolipoprotein B, systolic and diastolic blood pressure, weight, and fasting insulin than nonusers. IV. Contraindications to HRT Use Estrogen replacement therapy may be contraindicated in some women. Exogenous estrogens raise triglyceride levels [14]; women with hypertriglyceridemia (levels above 500 mg/dl) can experience elevations of triglycerides to 1000 mg/dl or more, and cases of hypertriglyceride-associated pancreatitis have been reported [ 15]. Oral estrogens are metabolized through the liver with a first-pass mechanism [ 16] and thus can affect clotting factors that are formed in the liver. Women with a history of deep vein thrombosis or pulmonary embolism are at increased risk of recurrence if they use estrogen replacement therapy [17-20] and so are advised to avoid HRT. Some women who have periods of immobilization as a result of trauma or surgery are advised to discontinue HRT temporarily [21 ]. Estrogens can be carcinogenic to various tissues, including the endometrium [10] and breast [22]. Thus, women who have been diagnosed with endometrial cancer are usually advised not to take estrogen therapy, although those with hysterectomytreated, well-differentiated, stage I carcinoma can probably be safely treated with estrogen plus progesterone therapy [23]. Women with adenomatous endometrial hyperplasia are advised not to use estrogen therapy if they have not undergone hysterectomy, but they are often prescribed progestin therapy to counteract endogenous estrogen stimulation of the endometrium [24]. Use of HRT is contraindicated for women with a history of breast cancer, although some clinicians treat menopausal symptoms with short courses of estrogens [25]. One study is testing HRT in 1100 hormone receptor-negative breast cancer patients in a randomized controlled clinical trial [26]. It is likely that long-duration use of HRT poses too large a risk of recurrence or new cancer development to be acceptable to most patients. Estrogen exacerbates endometriosis; thus, women with a history of severe endometriosis might have recurrence of endometriosis-related symptoms on estrogen therapy that is not opposed by progesterone [27]. Exogenous estrogen may be contraindicated in women with active gallbladder disease [28,29]. The Heart and Estrogen/Progestin Replacement Study (HERS) trial found almost a 40% increased risk (p = 0.05) of developing gallbladder disease after 4-5 years of follow-up in women with coronary disease randomized to combined estrogen-progestin therapy compared with placebo [20]. Estrogen therapy may also cause exacerbation of symptoms related to migraine headaches [30] and may increase risk of lupus flares [31 ]. V. Epidemiologic Studies HRT has been implicated as both beneficial and harmful to the health and quality of life for menopausal women. Many studies have examined the role of exogenous hormones in the development of hormone-dependent cancers, cardiovascular disease, and osteoporosis. As each relationship is summarized in the following sections, the decades during which women were using HRT in each study should be kept in mind. Use that occurred before the mid-1980s was almost exclusively estrogen replacement therapy. Since then, the standard treatment for

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symptoms of menopause has been combination HRT for women with intact uteri. Use of combination therapy has increased substantially since the 1980s [1,2] even though about 15 years have elapsed since combination HRT was first recommended for women who still have a uterus. A. Cancer 1. Breast Cancer

Early epidemiologic studies pointed to a role for hormones in the etiology of breast cancer; women who had early bilateral oophorectomy, a late age at menarche, or an early age at menopause were less likely to develop breast cancer than women who did not have these factors [22,32]. A combined analysis of six prospective studies supports the role of endogenous estrogens in the development of postmenopausal breast cancer [33]. The mean concentration of serum estradiol collected from postmenopausal women was 15% higher in those who subsequently developed breast cancer than in those who did not develop disease. Findings from the combined analysis of the case-control data were similar, but the test for heterogeneity across studies was statistically significant. Newer hypotheses focus on how specific reproductive events and exogenous and endogenous hormones affect breast cell proliferation and the accumulation of DNA damage [22]. There is an extensive epidemiologic literature regarding the relationship between exogenous menopausal hormone use and the risk of developing breast cancer. The Collaborative Group on Hormonal Factors in Breast Cancer combined original data from 51 epidemiologic studies to study the relationship between HRT use and breast cancer [34]. This collaborative investigation was estimated to include about 90% of the world's epidemiologic data on 52,705 women with breast cancer and 108,411 women without breast cancer. Because the average year of diagnosis for the women included in the collaborative analysis was 1985, the reported HRT and breast cancer associations were based primarily on the use of unopposed estrogen. Among women who were currently using HRT or who had stopped using HRT during the previous 1-4 years, the risk of breast cancer increased 2.3% for each year of HRT (95% confidence interval (CI) = 1.1-3.6). The increase in risk for each year of HRT use was hypothesized to be similar in magnitude to the effects of delaying menopause each year among women who have never used HRT. Among current and recent HRT users, the trend of increasing risk with increasing duration of use was significant, and women who had been using HRT for 15 or more years had a significantly elevated risk of 1.56 of developing breast cancer. The increase in risk was more pronounced among lean women than among women with high body mass index. However, women who used HRT had tumors that were less likely to have spread to axillary nodes and to distant sites than women who had never used HRT. The increased risk found for current and recent users was not seen among women who had stopped using HRT five or more years in the past, regardless of duration of use [34]. Among past users, risk estimates were 1.12 for women who used HRT for less than one and 1-4 years, 0.90 for women who used HRT for 5 - 9 years, and 0.95 for women who used HRT for 10 or more years. None of these estimates was statistically significant, and there was no trend in risk by time since last use.

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Only a few studies have examined the effects of estrogen plus progestin on breast cancer risk and, in aggregate, they do not provide sufficient evidence for making a judgment about a positive relationship [35-42]. In the collaborative analysis, risk estimates for combination therapy were elevated and were slightly greater than those for unopposed estrogen. However, none of the comparisons were significantly different than the risk for unopposed estrogen, and none differed significantly from one. Animal and in vitro studies have yielded conflicting results regarding the role for progestins in the development of breast cancer [22]. Animal studies suggest that addition of progestin to estrogen replacement therapy results in greater breast cell proliferation than estrogens alone whereas in vitro studies suggest an inhibitory effect of progestins. In summary, the collaborative study provides strong evidence for a relationship between HRT use, more specifically estrogen replacement therapy, and the risk of developing breast cancer [34]. The nonsignificant • tests for heterogeneity suggested that there was no variation in findings across studies and that no one study dominated the overall results. Risk increased with longer duration of use and decreased after stopping use; the increased effect was almost entirely absent about five years after stopping use. Additional studies are needed to address the long-term effects of combination HRT. Although the relationship between combination HRT use and breast cancer risk has been examined in a few studies, the existing evidence suggests that estrogen plus progestin use is unlikely to reduce risk and thus leaves open the question about whether combination HRT use increases risk or has no effect. In addition, because HRT use was associated with tumors that were less likely to have spread to axillary nodes and distant sites [34], more data are needed to examine the influence of HRT use on the virulence of breast tumors and on breast cancer survival. 2. Colorectal Cancer

Colorectal cancer is the third leading cause of cancer and cancer death in women after breast and lung cancer [43]. Several biologic mechanisms have been proposed for a possible protective effect of HRT on the risk of developing colon cancer: (1) a reduction in the concentration of secondary bile acids that have been hypothesized to initiate or promote malignancy in the colon [44] and (2) a loss of the tumor suppressor function on the estrogen receptor (ER) gene in epithelial colorectal tissue [45,46]. The preponderance of the epidemiologic literature available through 1994 as reviewed by Calle and colleagues [47,48] and several more recent studies [49-53] suggested an inverse relationship between HRT and the risk of developing cancer of the colon/rectum. Some studies found a relationship with duration of use [47,51,54], and other studies found that the reduction in risk was most apparent for women who were currently using HRT or had recently stopped using HRT [47,49,50,52,54,55]. Some epidemiologic studies reported reduced risks only for colon cancer, some reported reduced risks only for cancer of the rectum, and others found that risk was reduced for both sites [47]. However, not all studies found an inverse association (see review by Calle et al. [47]) [56-60]. A meta-analysis concluded that HRT use reduced the risk of developing colon cancer in women [61]. The random effects model yielded a significantly reduced risk of colon cancer for

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women who had ever used HRT (0.86, 95% CI = 0.73-0.99) and for women who had used HRT for more than five years (0.73, 95% CI = 0.53-1.02). The largest reduction in risk was for women who were current or recent HRT users (0.69, 95% CI = 0.52-0.91). Reduced risks appeared more pronounced in studies published since 1990 than in those published earlier. In order to refine our understanding of the relationship between HRT and cancers of the colon/rectum, laboratory investigations are needed to investigate the possible biologic mechanisms, and epidemiologic studies are needed to confirm the current hypothesis of a protective effect. The number of studies that examined exposure to HRT in detail and included dosage of HRT and multiple levels of duration of use and time since first or last use was limited. Future studies should include a complete assessment of potentially confounding factors and of the various measures of HRT in relation to the occurrence of colon cancer and, separately, of rectal cancer. 3. Endometrial Cancer

Endometrial cancer, or cancer of the lining of the uterus, is the fourth leading cause of cancer in women, accounting for about 36,100 new diagnoses each year, and it ranks seventh among the top ten cancer mortality sites [43]. Beginning with two reports in the New England Journal of Medicine in 1975, a substantial epidemiologic literature supporting an association between the development of endometrial cancer and use of estrogen replacement therapy has accumulated [7,8,62,63]. The risk related to unopposed estrogen use is at least twofold for ever use, increases with duration and dose, is consistent across many studies, and involves the direct effects of estrogen on hyperplastic changes to the endometrium [62,63]. Even low dose unopposed estrogen therapy (0.3 mg per day) carries some increased risk of this malignancy [64]. The increased risk of endometrial cancer associated with use of unopposed estrogens appears to persist for at least five years after stopping use, and according to a meta-analysis, women who used HRT had nearly three times the risk of dying from endometrial cancer as women who had never used HRT (2.7, 95% CI = 0.9-8.0) [63]. Findings from the Postmenopausal Estroge~Progestin Interventions (PEPI) Trial strongly support the use of progestin in combination with estrogen for women who still have a uterus [ 10]. In this randomized clinical trial, the histologic changes to the endometrium were examined among 596 postmenopausal women aged 45-64 years who received the placebo, 0.625 mg/ day conjugated equine estrogens (CEE) alone, CEE 0.625 mg/ day plus cyclic medroxyprogesterone acetate (MPA) 10 mg/day for 12 days/month, CEE 0.625 mg/day plus continuous MPA 2.5 mg/day, or CEE 0.625 mg/day plus cyclic micronized progesterone 200 mg/day for 12 days/month. Women who took only CEE were more likely to develop hyperplastic changes to the endometrium than women who used an estrogen plus progestin regimen. CEE plus cyclic or continuous MPA or CEE plus cyclic micronized progesterone provided protection against hyperplastic changes to the endometrium. Use of combination oral contraceptives provides protection from developing endometrial cancer that persists for at least 15 years after stopping use [65]. One study has examined whether use of oral contraceptives in the past results in different risks of developing endometrial cancer for women who have also used

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estrogen replacement therapy [66]. In this study, women who used estrogen replacement therapy for at least six years had a sevenfold statistically significant increased risk of developing endometrial cancer. When risks were examined by whether or not women had used oral contraceptives, risks were largest for women who had never used the pill. Although risks were lower for women who had used oral contraceptives, estrogen replacement therapy still appeared to increase their risk about twofold. These findings should be interpreted with caution due to the small number of cases who used both estrogen replacement therapy and oral contraceptives and require replication in other investigations. The existing literature with information about combination therapy and endometrial cancer includes only limited results regarding duration of use, cyclic versus continuous therapy, and specific doses of estrogen and progestin [67-73]. One study in Los Angeles found no increased risk of endometrial cancer among women who used continuous combination therapy [67]. In general, risk estimates for using estrogen plus progestin were lower than risks for using unopposed estrogen [67-69,71,72]. Of note, the lower estimates of risk for combination therapy were still elevated risks, particularly for cyclic progestin use of fewer than 10 days per month [67,69,71]. For example, in the case-control study conducted in western Washington State, the risk for using estrogen plus progestin therapy for less than 10 days per month increased from 2.1 (95% CI = 0.9-4.7) for 6 to 35 months use to 3.7 (95% CI = 1.7-8.2) for at least 60 months use [69]. The risks of using estrogen plus progestin therapy for 10 or more days per month for these same durations were 0.8 (95% CI = 0.4-1.8) and 2.5 (95% CI = 1.1-5.5), respectively. The study from Los Angeles reported significantly elevated risks for sequential combination therapy taken for fewer than 10 days per month and no increased risk for therapy of 10 or more days per month [67]. In summary, the positive relationship between unopposed estrogen therapy and the risk of endometrial cancer in women with a uterus is well established. The unanswered questions involve the long-term effects of combination therapy, the optimal regimen for progestin therapy (cyclic versus continuous, number of days, dosage, and type of progestin [MPA or micronized progesterone]), and any possible modification by prior oral contraceptive use or other risk factors for endometrial cancer. While the effects of estrogen plus progestin use on the endometrium appear to be different than those of estrogen alone, estrogen plus progestin therapy may also increase risk. 4. Ovarian Cancer

Ovarian cancer is less common than the other hormonerelated cancers in women but contributes disproportionately to cancer mortality [43]. Several hypotheses provide biologic plausibility for a relationship between ovarian cancer and HRT [74-76]. One hypothesis postulated that estrogen use might reduce the risk of ovarian cancer because estrogen lowers the production of pituitary gonadotropins [74,75]. Another theory posited that ovarian tumorigenesis occurred in two stages: (1) formation of inclusion cysts entrapped by ovarian surface epithelium into the ovarian stroma, followed by (2) estrogenstimulated proliferation and malignant transformation of the inclusion cysts [76].

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According to a collaborative analysis [77], two reviews that included cohort and case-control analyses of this relationship [78,79], and two more studies [80,81], the epidemiologic evidence for a relationship between ovarian cancer and HRT is unclear. Many studies showed no appreciable relationship but reported only on ever use of estrogen replacement therapy [81]. Some studies suggested the possibility of a slightly increased risk of ovarian cancer with longer duration of estrogen replacement therapy, but they generally did not yield a statistically significant risk estimate for the longest duration nor a significant trend [80,81]. A prospective study of fatal ovarian cancer and estrogen replacement therapy found a significant trend of increasing risk with increasing duration of use [80]. The pooled analyses of the hospital- and population-based case-control studies available before 1992, which included large numbers of cases (406 and 824 cases respectively), did not find a trend of increasing risk of epithelial ovarian cancer with increasing duration of use [77]. These findings did not differ by menopausal status or histologic diagnosis. A meta-analysis of the relationship between HRT and the risk of developing ovarian cancer found that women who had ever used HRT had a slightly elevated risk of developing ovarian cancer (1.15, 95% CI = 1.05-1.27), and women with more than ten years of use had the highest risk (1.27, 95% CI = 1.00-1.61) [82]. At the p = 0.10 level of statistical significance specified by the investigators for assessing the consistency of findings across studies, the tests for heterogeneity for ever use and for long duration of use were statistically significant. Three studies reported a relationship between noncontraceptive estrogen use and specific histologic subtypes of epithelial ovarian tumors [78,83,84]. These studies reported two- to threefold statistically significant or marginally significant increased risks for endometrioid tumors among women who had ever used noncontraceptive estrogens. In the Canadian study [78], women who used estrogen replacement therapy for at least five years had the following risks of developing specific types of tumors: 2.03 (95% CI -- 1.04-3.97) for serous ovarian tumors, 2.81 (95% CI -- 1.15-6.89) for endometrioid tumors, and 0.58 (95% CI = 0.08-4.21) for mucinous tumors. Another study did not confirm different risks by histologic subtype [85]. Women who have used oral contraceptives have a reduced risk of ovarian cancer that persists for at least 15 years after stopping use [86]. Two studies examined whether the relationship between ovarian cancer risk and use of noncontraceptive estrogen varied by prior use of oral contraceptives [66,78]. Women who had never used oral contraceptives but had used HRT had a threefold significantly elevated risk of epithelial ovarian cancer; by comparison, the risk associated with HRT use among women who had used oral contraceptives in the past was reduced [66]. In the Canadian study, the trend for using estrogen replacement therapy increased significantly among women who had never used oral contraceptives [78]. The trend for estrogen replacement therapy among women who had used oral contraceptives in the past was in the same direction as for never users but was not significant. The findings from both studies were based on small numbers of cases exposed to both estrogen replacement therapy and oral contraceptive use and should be interpreted with caution.

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In summary, the question of an association between estrogen replacement therapy and ovarian cancer remains unanswered, although HRT does not appear to reduce the risk of ovarian cancer. There are several important research questions that deserve further investigation in addition to the basic question. First, what is the relationship between ovarian cancer and combination therapy (estrogen plus progestin use) for women who still have a uterus? Second, does risk vary by histologic diagnosis, specifically between mucinous versus endometrioid or serous ovarian tumors? Finally, is risk different for women who have used oral contraceptives in the past or for women vChohave other long-lasting risk factors? B. Cardiovascular Disease

1. Coronary Heart Disease Risk of atherosclerosis increases after menopause or bilateral oophorectomy [87]. The majority of epidemiologic observational studies note a benefit from estrogen against coronary heart disease [88-90], coronary death [90-92], and all-cause mortality [93,94]. Overall, epidemiologic evidence indicates a 30-50% reduction in risk of coronary heart disease among postmenopausal women who use estrogen therapy [88]. In the Nurses' Health Study, women who used estrogen alone had a 40% reduction (95% CI = 17%-57%) in risk of major coronary heart disease (nonfatal myocardial infarction, coronary death); the comparable risk reduction for users of combined therapy was 61% (95% CI = 22-81%) [90]. This effect was attenuated, however, in long-term users and was not present in past users. Furthermore, the reduction in risk was greater in younger than in older women. Coronary revascularization procedures were equally common in current users compared to never-users of postmenopausal estrogen therapy, which could indicate a healthy user effect. Thus, women using HRT might have more access to early diagnosis and invasive therapy of coronary disease compared with nonusers. A prospective cohort study in Sweden involved the linkage of hormone prescriptions dispensed during 1977-1980 to central health records (1977-1983) of the entire Uppsala female population of 1.4 million women aged 35 and older [95]. The age-adjusted relative risk of myocardial infarction in hormone users was 0.81 (95% CI = 0.7-0.92). Women who used the more potent estrogens (CEE or estradiol) had lower risks than women who had used other estrogens. The addition of the progestin levonorgestrel to estradiol did not alter the protective effect of estradiol. As with the Nurses' Health Study, the protective effect for cardiovascular disease associated with hormone use was greater in younger than in older women. The mechanisms for the hypothesized improvement in cardiovascular disease risk with estrogen therapy may be multifactorial. Exogenous estrogen increases HDL and lowers LDL cholesterol [14,96]. In an analysis of the PEPI Trial, serum measures of cardiovascular disease were examined in 875 postmenopausal women who were randomized to placebo or one of four HRT regimens, described previously. After three years of treatment, investigators found mean increases in plasma HDL cholesterol of 1.2-5.8 mg/dl in women randomized to combined hormone therapy or unopposed estrogen compared with a decrease of 1.2 mg/dl in placebo-treated women, with the largest

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benefit observed for unopposed estrogen. Significant lowering of LDL and total cholesterol was also observed in the activetreatment groups. The beneficial effects of estrogen were blunted with the addition of progestins. Decreases in fibrinogen and antithrombin III, and increases in plasminogen, factor X, and factor VII, have been found in various randomized trials of HRT [ 14,97,98]. Estrogen also has direct beneficial effects on the coronary arterial wall in humans; it improves blood flow [99-102] and has antioxidant properties that may slow early stages of atherosclerosis [ 103]. Conversely, progest~s may reverse the direct benefits of estrogen on coronary vasculature [ 104,105]. The effect of HRT on recurrent coronary heart disease and other cardiovascular disease was tested in 2763 postmenopausal women (mean age 66.7 years) with a documented history of coronary disease in the Heart and Estrogen/Progestin Replacement Study (HERS) [20]. HERS was a randomized, blinded, placebo-controlled clinical trial of an average of 4.1 years treatment with either combined 0.625 mg CEE plus 2.5 mg MPA daily or placebo medication. Pre-existing coronary disease was defined as evidence of one or more of myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary revascularization, or angiographic evidence of I>50% occlusion of one or more major coronary arteries. Despite a net 11% lower LDL cholesterol and 10% higher HDL cholesterol level in the HRT arm compared with placebo (p < 0.001), there was no significant difference between groups in occurrence of myocardial infarction or coronary death (relative hazard 0.99, 95% CI -0.80-1.22). There were no significant differences between groups in incidence of other cardiovascular outcomes (coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease). There was a statistically significant time trend; more coronary events were observed in the HRT arm compared to the placebo arm in year 1 of follow-up, and fewer events were observed in the HRT arm in years 4 and 5 of follow-up. 2. Stroke

The data on HRT effect on stroke incidence are unclear. Among the published observational cohort studies of HRT use and stroke incidence or death [ 106], three studies found a statistically significant decrease in risk of stroke among HRT users [107-109], and one found a small but statistically significant increase in risk [ 110]. In the Nurses' Health Study, little association between HRT use and stroke occurrence was observed for ever use of estrogens (1.27, 95% CI = 0.95-1.69). Most of the increased risk was in ischemic stroke (1.4, 95% CI = 1.02-1.92) [90]. In the HERS trial, the incidence of stroke did not differ significantly between women randomized to HRT and those assigned to placebo (relative hazard 1.13, 95% CI -- 0.851.48) [20]. It is difficult to predict the effect of HRT, either unopposed estrogen or combination therapy, on coronary or other cardiovascular diseases. Some lipid and coagulation factor changes (LDL-C, HDL-C, fibrinogen, plasminogen) could reduce risk of cardiovascular disease, while others (triglycerides, factor VII, factor X, antithrombin III) could increase cardiovascular disease

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risk [ 106]. Beneficial effects of estrogen on the cardiovascular system may be lessened by the addition of progestins [106]. Finally, the degree of protection afforded to intermediate outcomes such as lipids and coagulation factors may not translate into that degree of protection against cardiovascular disease occurrence [ 111 ]. There are several major unresolved issues surrounding the association between HRT use and risk of cardiovascular disease. The effect of lipid and coagulation factor changes with HRT use on clinical endpoints is unknown for healthy women. It does not necessarily follow that improvement in lipid fractions will translate into improvement in clinical disease risk. As described in Section III, women who use HRT are more likely to follow health practices that protect against atherosclerosis and its sequelae compared with women who do not use HRT. The need for large, controlled, randomized clinical trials of HRT and clinical endpoints is supported by results from the HERS trial. Observational data indicated that HRT would be protective against cardiovascular disease recurrence and mortality in women with preexisting coronary heart disease [94,112-114]. The HERS trial found no benefit, and considerable risk, for HRT use among women at high risk for coronary events and death [20]. The HERS results, however, should not be extrapolated to unopposed estrogen therapy and HRT used for primary prevention [115]. 3. Venous Thromboembolic Disease

There is evidence that oral estrogen therapy increases risk of pulmonary embolism and deep vein thrombosis in postmenopausal women. Three large prospective studies found that current, but not past, HRT users had a statistically significant twoto threefold increased risk for pulmonary embolism and deep vein thrombosis [ 17-19]. The risk was highest in the first few years of use and was increased for both unopposed estrogen therapy and combination therapy. This is consistent with a procoagulant mechanism of estrogen that is not counteracted by progestins. Other exposures, such as smoking, did not affect the relationship between HRT and risk of thromboembolic disease. The HERS clinical trial found that HRT use increased risk of venous thromboembolic disease nearly threefold (relative hazard 2.89, 95% CI = 1.50-5.58). The risk was greatest in the first year of follow-up (relative hazard 3.29, 95% CI = 1.0710.08), but the relative hazard did not go below 2.05 in 4 - 5 years of follow-up. It has been postulated that transdermal and other nonoral HRT preparations will pose less risk of thromboembolic disease because of bypassing the liver pathway [ 116], largely because of small trial evidence that transderrnal estrogen does not elevate renin substrate or change levels of the clotting factors fibrinopeptide A, high-molecular weight fibrinogen, antithrombin III activity, or antithrombin III antigen [ 117]. There has not been a clinical trial of transdermal estrogen of sufficiently large scale to assess effects on clinical thromboembolic disease clinical endpoints, nor are there large-scale, long-term observational data to support this. It is also not clear if the increased risk of thromboembolic disease associated with oral HRT applies to all women, or to specific subgroups with other risk factors such as obesity, history of clotting disorders, or a family history of thromboembolic disease.

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C. Osteoporosis On average, women lose 1% of bone mass per year in the first few years after menopause, and the risk of fracture increases fourfold for each 1 standard deviation decline in bone density at the hip [ 118]. This bone loss is thought to result from the loss of ovarian estrogens at menopause. Estrogen stabilizes bone mineral density [107,119,120], and many observational studies support a 30-50% reduction in fracture rates in women who use postmenopausal estrogen long-term compared with nonusers [ 121]. Estrogen is one of the drugs approved by the Food and Drug Administration (FDA) for the prevention and treatment of osteoporosis [ 122]. The timing of estrogen use for optimal protection is important. Observational data suggest that use during the period of risk for fractures (e.g., over age 75) is most protective, regardless of whether estrogen was used earlier at the time of menopause [121,123,124]. In the Study of Osteoporotic Fractures, current estrogen users who had started estrogen within five years of menopause had a 70% decreased risk of hip fracture and wrist fracture and a 50% decreased risk of all nonspinal fractures [ 121]. Previous estrogen use for more than ten years and use begun soon after menopause did not confer this protection if the woman was not a current estrogen user. Analysis of data from 670 women who had bone mineral density measurements in the Framingham cohort indicated that women should take estrogen therapy for at least seven years after menopause to receive benefit to bone density [ 123]. The data also indicated that duration of therapy of this length may be insufficient to protect the oldest, highest risk women over age 75 years. The HERS trial found no reduction in incidence of hip or other fracture in women randomized to HRT compared with those randomized to placebo, although the study may not have had sufficient power to detect meaningful differences in fracture rates between the two arms [20].

D. Menopausal Symptoms Approximately 20% of women seek medical care for symptoms of menopause [125,126]. As a result of declining circulating levels of estrogen, women may experience vasomotor symptoms that consist of hot flashes, night sweats, irritability and other emotional symptoms, vaginal symptoms including dryness and difficulty with sexual functioning, and urinary tract symptoms. Most menopausal symptoms have been shown in short-term (one year or less) randomized placebo-controlled clinical trials to be dramatically relieved with estrogen or combined estrogen plus progestin [127]. Acute relief of vasomotor symptoms has been demonstrated in laboratory settings [127]. The use of HRT, however, presents its own set of symptoms that may or may not be tolerated by women. Women using either estrogen alone or in combination with progestin can be subject to vaginal spotting or bleeding. Use of a cyclic progestin preparation results in regular bleeding similar to that of regular menstrual cycling [24]. Use of unopposed estrogen or estrogen plus continuous progestin preparations often results in unscheduled vaginal spotting or bleeding [24,128]. Other symptoms may include breast tenderness, headache, bloating, and depression (from progestins) [129]. The most commonly reported rea-

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sons for women stopping hormone therapy include vaginal bleeding and breast tenderness, in addition to concerns about cancer risk [ 130,131 ].

E. Cognitive and Memory Dysfunction Alzheimer's disease is the most common dementia of older women, affecting 3-11% of community residents over age 65, with the highest prevalence in the oldest old [132,133]. Most studies of dementia and HRT have been observational in design, which can lead to biased conclusions as women with higher levels of cognition may be more likely to take or be prescribed HRT [ 134]. In these observational studies, HRT users have been found to have lower risk of Alzheimer's disease [135], fewer deaths related to Alzheimer's disease or related dementia [109], higher scores on the Mini-Mental State Examination [ 135], and delayed onset of Alzheimer's disease [136]. In the Rancho Bernando Study, no effect of postmenopausal estrogen therapy on cognitive performance was observed [ 137]. In a short-term clinical trial, women on placebo showed a decrease in immediate and delayed recall of paired-associates following surgical menopause, compared with no change in estrogen-treated women [138]. Another placebo-controlled clinical trial failed to demonstrate cognitive benefits from low-dose transdermal estradiol [139]. Several small estrogen treatment trials (most open-label) report a significant improvement of Alzheimer's symptoms among estrogen-treated women [140,141]. Estrogen might protect against dementia through several mechanisms. Estrogen suppresses levels of apolipoprotein E, a risk factor for late-onset Alzheimer's disease [142], favorably regulates the production of Alzheimer amyloid precursor protein [142], and has antiinflammatory properties that could protect brain tissue [ 143]. It stimulates production of basal forebrain cholinergic neurons [144,145], may work in concert with neurotrophins to regulate protein synthesis necessary for neuronal differentiation [146], and may improve cerebral perfusion [147].

F. All Cause Mortality Numerous studies that have assessed the effects of HRT on all-cause mortality have consistently found a protective effect [53,73,91-93,148-152]. In general, the risk of death from all causes was lower by 20-50% for women who had used HRT compared to women who had never used menopausal hormones. The reduction in risk has been attributed primarily to the reduced risk of dying from coronary heart disease. However, because lower mortality rates have also been reported for conditions that are generally not believed to be associated with hormone use, other explanations need to be considered [153]. Possible explanations include: (1) multifactorial biologic effects of estrogen and (2) bias introduced through the selective use of estrogen by women who have a low cardiovascular risk profile and who practice healthy behaviors [ 153].

VI. Selective Estrogen Receptor Modulator Drugs (SERMS) Estrogen enters target cells by diffusing through the outer cell membrane, then binds to the nuclear estrogen receptor (ER), and

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thus gains entry to the cell nucleus where it has direct effects on cell transcription [154]. Several pharmaceutical preparations, manufactured chemicals, and naturally occurring substances act at the level of the ER as either estrogen agonists or antagonists [155]. Tamoxifen, a first-generation SERM, has been successfully used to treat estrogen-receptor-positive breast cancer and has been found to reduce risk of death by 25% in node-positive, ER-positive breast cancer patients using the medication for five years after diagnosis [ 156]. Breast cancer patients using Tamoxifen were also noted to have about a one-third lower incidence of new primary breast cancers [ 157], which led to the hypothesis that Tamoxifen might be useful in the primary prevention of breast cancer in high-risk women [ 158]. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial released main trial results, which showed that high-risk women randomized to Tamoxifen for five years had a 45% decrease in incidence of breast cancer compared with women randomized to placebo [159]. Two smaller European clinical trials (7879 women) found no difference in rates of breast cancer occurrence between women randomized to Tamoxifen and women randomized to placebo [ 160,161 ]. Results of a two-year randomized placebo-controlled trial of Raloxifene (a SERM) versus placebo in 7705 postmenopausal women at normal risk for developing breast cancer showed a 66% reduced risk for breast cancer in the group randomized to Raloxifene [162]. Tamoxifen has been found to be proestrogenic at the level of the cardiovascular system [163], bone [ 164,165], and endometrium [ 166,167]. This action is reflected in the reduced incidence of cardiovascular disease and osteoporotic fractures and the increased incidence of endometrial cancer in women taking Tamoxifen either for breast cancer treatment [ 168] or in the prevention trials [ 159,163]. Raloxifene may have similar effects on the cardiovascular and bone systems [ 169,170] but appears to be antiestrogenic at the endometrium [ 171 ] and so theoretically should not increase risk for endometrial cancer. Raloxifene has been found to increase bone density in postmenopausal women [169] and is now FDA approved for the treatment and prevention of osteoporosis. The NSABP Study of Tamoxifen and Raloxifene (STAR) will compare these two SERMS on the incidence of primary breast cancer in 22,000 high risk postmenopausal (natural or surgical) women who will be randomized to Tamoxifen or Raloxifene for five years, and followed for at least two additional years [162]. This study will also assess the effect on risk of cardiovascular disease, fractures, toxicity, and adverse events. Several other SERM preparations are in Phase I or II trial testing [172].

VII. Summary and Future Research

A. Conclusions and Effects of Bias HRT is used extensively in the United States [1,2] and has been prescribed for some women for the rest of their lives to prevent or treat specific conditions [ 173]. In addition to the beneficial influence of HRT on treating symptoms of menopause, estrogen replacement therapy has been associated with lower mortality and longer survival and may decrease the risk of coronary heart disease, osteoporosis, and possibly colon cancer. On the negative side, estrogen replacement therapy likely increases

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the risk of breast cancer, endometrial cancer, deep vein thrombosis, and pulmonary embolism. The effects of estrogen replacement therapy on ovarian cancer, stroke, and cognitive and memory dysfunction seem less clear. Selection biases need to be considered in the interpretation of observational studies about HRT. The possibility that women who take estrogen have fewer cardiovascular risk factors and are more likely to practice healthy dietary and exercise behaviors raises concerns that the beneficial effects on the coronary heart disease as seen in observational studies may be overestimated [12,153,174]. Similarly, women who suffer from hot flashes and other symptoms of menopause likely have lower levels of endogenous estrogens and hence may have a lower risk of developing breast cancer [22]. Because these women are also more likely to use menopausal estrogens, their inclusion in studies of HRT and breast cancer could lead to an underestimate of the adverse effects of HRT on this disease. In addition, HRT prescribing practices may have further complicated the ability to address this concern because the various contraindications over time suggested prudence in prescribing HRT for women who had risk factors or were not in good health [ 174]. The resolution of such issues can only be addressed in a randomized trial.

B. Unanswered Questions Because the use of combination HRT increased substantially only since the 1980s [2], the published literature does not provide information about the long-term effects of combination HRT. Future studies should examine the effects of combination HRT on the occurrence, mortality, and survival from the cardiovascular diseases, hormone-dependent cancers, and selected other conditions. The minimum effective dose is not known [ 173]. In order to specify the optimum duration of therapy required to maximize benefits and to decrease risks, future investigations should include data about the length of time from starting use to an increased/decreased risk and about the length time that risk/benefit persists after stopping use. Little is known about how much progestin to take each month and whether to use progestin sequentially or at the same time as estrogen. There are only limited data about the number of progestin pills to take each month (e.g., 10 pills, more than 10 pills, or every day). Additional data are needed to clarify which subgroups of women are most likely to benefit from using HRT. Before ages 55-59 years, breast cancer mortality is of greater concern than heart disease (Fig. 93.2). At older ages, cardiovascular mortality overwhelms mortality from other hormone-dependent conditions.

C. The Women's Health Initiative (WHI) The many open questions regarding the risks and benefits of long-term use of HRT prompted the funding in 1992 of the WHI Clinical Trial [ 122]. The WHI comprises three clinical intervention trials: HRT, calcium/vitamin D, and low-fat dietary modification. Women were recruited during 1993-1998 from diverse racial, ethnic, and geographic groups to 40 clinical centers across the United States. In the HRT trial, 27,500 postmenopausal women aged 50-79 years have been randomized to HRT or placebo. Women with a uterus are randomized in equal proportions to either placebo or combined estrogen plus progestin

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1800 1600 1400 1200

Coronaryheart disease

-"

Pulmonaryembolism and deep venous thrombosis

=-

Stroke

/

- - El- - Breast cancer

t /

- - ~ - - Colorectal cancer

g o

-"

/ll /

/

i i : i i Co~rPrlaSnU~:ri~rcancer

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50-54

55-59

60-64

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75-79

80-84

Age at death

Fig. 93.2 Age-specific cardiovascular and cancer mortality rates, females, U.S., 1995.

(CEE 0.625 mg/day plus MPA 2.5 mg/day). Women who have previously undergone hysterectomy (45% of the cohort) are randomized in equal proportions to either placebo or unopposed estrogen (CEE 0.625 mg/day). Women are followed semiannually for 9 - 1 2 years for the occurrence of specific endpoints (coronary heart disease, coronary deaths, other cardiovascular disease, breast and other cancers, and osteoporotic fractures). The WHI will provide definitive answers about the effect of HRT on preventing coronary heart disease and osteoporotic fractures and the potential adverse effects on risk of breast and other cancers, thromboembolic disease, and other measures of health and disease. It will provide these answers without the bias that is present in observational studies from health, lifestyle, and socioeconomic differences between HRT users and nonusers. The WHI Memory Study, an ancillary study to the WHI HRT trial, is designed to assess the effects of HRT on the development and progression of symptoms associated with dementia [134]. This study will assess cognition at baseline and follow-up (9-12 years) in participants aged 65 and older at randomization using the Mini-Mental State Examination. Participants with low scores will undergo more intensive neuropsychological testing and neuropsychiatric examinations to classify women to dementia status. It is hypothesized that dementia-related symptoms will be delayed in women who are on active (estrogen or combined estrogen plus progestin) therapy as compared to placebo. In summary, only a randomized trial such as the WHI can provide assurances about the long-term effects of HRT. In the meantime, a woman and her health care provider should discuss her family history of diseases and other individual risk factors and weigh her possible risks and benefits of HRT, SERMS, and other treatment modalities, including but not limited to taking low dose aspirin, controlling coronary risk factors (e.g., blood pressure, diabetes), taking calcium/vitamin D or alendronate for

prevention of osteoporotic fractures [ 175], and adopting healthy behaviors such as dietary modification, regular physical activity, avoidance of tobacco and excess alcohol, and maintenance of a healthy body weight. References

1. IMS America (1998). Top 200 drugs of 1997. Pharm. Times 64(4), 31-49. 2. Wysowski, D. K., Golden, L., and Burke, L. (1995). Use of menopausal estrogens and medroxyprogesterone in the United States. Obstet. Gynecol. 85(1), 6-10. 3. Brett, K. M., and Madans, J. H. (1997). Use of postmenopausal hormone replacement therapy: Estimates from a Nationally Representative Cohort Study. Am. J. Epidemiol. 145(6), 536-545. 4. Hemminki, E., Kennedy, D. L., Baum, C., and McKinlay, S. M. (1988). Prescribing of noncontraceptive estrogens and progestins in the United States, 1974-86. Am. J. Public Health 78(11), 1479-1481. 5. Ellerington, M. C, and Whitehead, M. I. (1991). Hormone replacement therapy and its current use in British specialist clinical practice. In "Hormone Replacement Therapy and Breast Cancer Risk" (R. D. Mann, ed.), pp. 18-20. The Parthenon Publishing Group, Park Ridge, NJ. 6. Kennedy, D. L., Baum, C., and Forbes, M. B. (1985). Noncontraceptive estrogens and progestins: Use patterns over time. Obstet. Gynecol. 65(3), 441-446. 7. Smith, D. C., Prentice, R., Thompson, D. J., and Herrmann, W. L. (1975). Association of exogenous estrogen and endometrial carcinoma. N. Engl. J. Med. 293, 1164-1167. 8. Ziel, H. K., and Finkle, W. D. (1975). Increased risk of endometrial carcinoma among users of conjugated estrogens. N. Engl. J. Med. 293, 1167-1170. 9. Gambrell, R. D. (1982). The menopause: Benefits and risks of estrogen-progestogen replacement therapy. Fertil. Steril. 37, 457 -474.

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