THE RISE AND FALL OF MENOPAUSAL HORMONE THERAPY

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1 Annu. Rev. Public Health : doi: /annurev.publhealth Copyright c 2005 by Annual Reviews. All rights reserved THE RISE AND FALL OF MENOPAUSAL HORMONE THERAPY Elizabeth Barrett-Connor, 1 Deborah Grady, 2 and Marcia L. Stefanick 3 1 Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, California ; ebarrettconnor@ucsd.edu 2 Department of Epidemiology and Biostatistics, University of California, San Francisco, California 94105; dgrady@itsa.ucsf.edu 3 Stanford Prevention Research Center, School of Medicine, Stanford University, Stanford, California 94305; stefanick@stanford.edu Key Words estrogen therapy, menopause, heart disease, stroke, breast cancer Abstract Clinical trials show that hormone therapy (HT) is an effective treatment for vasomotor symptoms and vaginal dryness. HT improves other symptoms including sleep and quality of life in women who have menopause symptoms. In the Women s Health Initiative controlled clinical trials, both estrogen therapy (ET) and estrogen plus progestin therapy (EPT) reduced fracture risk, neither reduced the risk of heart disease, and both increased the risk of stroke, deep vein thrombosis, and dementia. EPT, but not ET, increased breast cancer risk and reduced colon cancer risk. Differences between EPT and ET may reflect chance, baseline differences between the EPT and ET cohorts, or a progestin effect. Studies of younger women and lower HT doses with intermediate endpoints are beginning. INTRODUCTION The prescription of estrogens to relieve menopause-related symptoms was approved by the Food and Drug Administration (FDA) more than 60 years ago. Over the years, enthusiasm for hormone therapy (HT) has fluctuated dramatically. As expectations of benefit increased in the 1960s, widespread estrogen use was advocated to prevent postmenopausal estrogen deficiency and the tragedy of the menopause (99). In the 1970s prescriptions decreased, reflecting public awareness of an increase in endometrial cancer in hormone users (84, 100) and subsequently increased again with evidence that the addition of a progestin could prevent estrogen-induced endometrial changes. In the 1980s there was a renewed emphasis on potential long-term benefits, as epidemiological evidence mounted for /05/ $

2 116 BARRETT-CONNOR GRADY STEFANICK a reduced risk of osteoporotic fractures (66, 96) and an equally dramatic reduction in coronary heart disease (18, 88). In 1992, a landmark systematic review and meta-analysis of the results of observational studies of postmenopausal HT described four outcomes plausibly related to HT: heart disease, hip fracture, breast cancer, and uterine cancer (32). On the basis of summary odds ratios from the observational studies and lifetable models, the authors concluded that the reduced risk of heart disease and hip fracture would outweigh the cancer risks. This favorable risk benefit ratio, based on observational evidence and driven largely by the apparent cardiovascular benefit, increased the recognition that coronary heart disease was the main killer of women, and led to the recommendation that hormone replacement therapy be considered for all women. In the United States, by the mid-1990s, recommendation of HT was counted as a criterion for good medical practice in managed care organizations, the annual number of HT prescriptions filled increased from 58 million in 1995 to 90 million in 1999 (43), and estrogen became the biggest selling prescription drug. By 2002, however, results from two large, randomized, placebo-controlled clinical trials, Heart and Estrogen/Progestin Replacement Study (HERS) and the Women s Health Initiative estrogen plus progestin trial (WHI-EPT), both comparing conjugated equine estrogen (CEE) plus daily medroxyprogesterone acetate (MPA) with placebo, did not show the expected coronary benefit (49, 75). Postmenopausal estrogen prescriptions decreased by 33% and combined estrogen/progestin therapy prescriptions decreased by 66%, with total hormone prescriptions dropping by 50% as shown in Figure 1 (43). In April of 2004, the main results from the Women s Health Initiative trial of unopposed estrogen (WHI-ET), which compared unopposed CEE with placebo, also reported no reduction in risk of coronary events, with as yet unknown effects on future hormone use (6). This chapter reviews the major randomized, placebo-controlled clinical trials of hormone therapy published in the past 10 years, first in a section most relevant to the management of menopause-related symptoms, and second in a section related to common chronic diseases possibly related to estrogen use. We also briefly describe large cohort studies and meta-analyses of observational data because volunteers in trials may differ from women in the community, outcome collection methods differ, and larger and longer observational studies provide information about rare events and about the risks and benefits of extended use. Because of space limitations, we do not discuss laboratory evidence for favorable or unfavorable outcomes. Finally, because postmenopausal hormone therapy is pharmacologic not physiologic, we do not use the term hormone replacement therapy. Instead we use hormone therapy (HT) as a comprehensive term for postmenopausal estrogen with or without a progestin, estrogen therapy (ET) to describe unopposed estrogen, and estrogen plus progestin therapy (EPT) to describe continuous or cyclic combined therapy.

3 MENOPAUSAL HORMONE THERAPY 117 Figure 1 Annual number of U.S. prescriptions for hormone therapy by formulation, 1995 to July Data taken from the National Prescription Audit Plus, IMS HEALTH. Abbreviations: HERS, Heart and Estrogen/Progestin Replacement Study; WHI, Women s Health Initiative. Permission to reprint from Hersch AL, Stefanick ML, Stafford RS National use of postmenopausal hormone therapy. JAMA 291:47 53 (43, figure 3, p. 50). Copyright c 2004 American Medical Association. All rights reserved. HORMONE THERAPY FOR MENOPAUSE-RELATED SYMPTOMS Vasomotor and genital symptoms are the symptoms most unequivocally associated with menopause and are consistently shown in clinical trials to respond better to estrogen than to placebo (58). As described below, other common complaints often attributed to menopause, such as mood swings, depression, disturbed sleep, and fuzzy thinking, are either unchanged by HT in controlled trials or are improved primarily or exclusively in women who have severe vasomotor symptoms. Vasomotor Symptoms Hot flashes, sudden waves of heat sensation typically spreading over the upper body and face, are experienced by about 75% of U.S. and European women at some point in the menopause transition (52, 91). Hot flashes tend to decrease in severity and frequency over a few months to a few years (53) but sometimes persist into old age. Severe hot flashes may compromise quality of life by causing discomfort, as well as embarrassing visible changes in skin color and sweating; severe night sweats may require change of bedding and interfere with sleep.

4 118 BARRETT-CONNOR GRADY STEFANICK Clinical Trials of HT for Vasomotor Symptoms Estrogen is the most effective treatment for troublesome vasomotor symptoms. The first systematic review of randomized controlled clinical trials found 40 trials showing that HT reduces the severity of vasomotor symptoms, often with improvement beginning within the first week of treatment (76). Summary estimates of hot-flash frequency and severity from another meta-analysis of the results of 21 trials of 3 months 3 years duration reported that standard doses of estrogen (equivalent to about mg of conjugated estrogen) reduced weekly hot-flash frequency by 77%, compared with placebo (58). Unopposed estrogen and estrogen plus progestin regimens were equally effective in relieving hot flashes in periand postmenopausal women, as were various types of estrogen, both oral and transdermal (58). Lower-than-standard doses of estrogen, such as 0.3 mg/day oral conjugated estrogen (93) and 0.02 to mg/day transdermal 17-beta estradiol (87, 92), are also effective for treatment of hot flashes. Many of these trials included only women who were compliant with HT in the analysis. Studies limited to compliant women tend to overestimate benefit and underestimate side effects. Estrogen therapy also appears to be effective in older women who have had hot flashes for many years. The 3-year Postmenopausal Estrogen/Progestin Intervention (PEPI) trial, which included 875 women who were within 10 years of menopause (average age 56), showed a 58% reduction in vasomotor symptoms in women receiving ET (alone or combined with a progestin) compared with placebo (35). In the Heart and Estrogen/Progestin Replacement Study (HERS), 85% of the 434 women (average age 67) who reported hot flashes at baseline improved after 1 year of hormone therapy, compared with 48% of women assigned to placebo (44). In the WHI-EPT trial, a subset of 1072 women in the EPT group and 974 women in the placebo group reported moderate-to-severe vasomotor symptoms at baseline. After 1 year, 77% in the hormone group had reduced severity of hot flashes, compared with 52% in the placebo group (40); more women assigned to active treatment also showed improvement in the severity of night sweats (71% compared with 53% in women assigned to placebo) (40). Quality of Life, Sleep, Mood, and Depression Results from randomized placebo-controlled trials suggest ET improves quality of life, as estimated by standard quantitative tests (76). This improvement in general quality of life is likely due to improvement in vasomotor symptoms (44). For example, in the HERS trial, improved quality of life related to EPT was limited to women who had vasomotor symptoms; women who reported no vasomotor symptoms at baseline also reported no improvement in quality of life on EPT and, in fact, reported less vigor and well-being than did women assigned to placebo (44). Among HERS women who reported trouble sleeping before treatment, a slightly higher proportion on EPT (39%) than on placebo (33%) reported improvement after 1 year (44). In WHI-EPT, EPT was associated with a statistically significant small

5 MENOPAUSAL HORMONE THERAPY 119 benefit in terms of sleep disturbance, physical functioning, and bodily pain at one year; however, these differences were not clinically meaningful (the mean benefit of sleep disturbance was 0.4 point on a 20-point scale, physical functioning was 0.8 point on a 100-point scale, and pain was 1.9 points on a 100-point scale). No differences were seen at three years between the women assigned to EPT versus placebo with regard to any quality-of-life outcome (40). In a subset analysis, 574 women aged who reported moderate-to-severe vasomotor symptoms at baseline showed a significant improvement in sleep disturbance on EPT versus placebo, with no difference in other quality-of-life outcomes (40). Feeling depressed is a common complaint during the menopause transition. Evidence that HT improves depressed mood is mixed. A 1997 review of 14 clinical trials (101) concluded that estrogen therapy improved depressed mood during the menopause transition or after oophorectomy, but the review included several clinical trials without placebo controls. In another review, significant improvement in mood was reported in the majority of 13 observational studies of nondepressed women, but half of the 14 clinical trials found no significant improvement in mood (62). The most recent review included 9 trials of ET for diverse depressive disorders among women in the menopause transition; 6 of these were placebo controlled, and 4 suggested that ET was superior to placebo (86). The most impressive results were reported from two trials of transdermal estrogen in the treatment of severe clinical depression (78, 85). In the HERS trial, emotional health was improved by ET only in women with vasomotor symptoms at baseline. In this trial of 2763 older women, 3 years of EPT had no significant effect on depressive symptoms overall; but women with flushing who were assigned to EPT experienced significantly fewer depressive symptoms and reported improved mental health compared with women with flushing in the placebo group (44). In contrast, the same combined-hormone treatment had no effect on an 8-item depression score in the overall WHI-EPT cohort or in the subset of 574 women aged who reported moderate-to-severe vasomotor symptoms at baseline (40). Weight Gain One clinical trial has demonstrated that weight gain during the menopause transition can be prevented by diet and exercise (54). In that trial, premenopausal women ages were randomly assigned to a lifestyle intervention of reduced calories and saturated fat plus increased physical activity or to assessment only. Although the proportion of women who became menopausal over the 5-year period is not reported, 55% of the lifestyle intervention participants were at or below baseline weight compared with 26% of controls after 4.5 years, and the mean weight in the intervention group was 0.1 kg below baseline compared with an average gain of 2.4 kg in the control group; waist circumference decreased 2.9 cm in the intervention group compared with a decrease of 0.5 cm in the control group.

6 120 BARRETT-CONNOR GRADY STEFANICK A quantitative review (68) of 22 randomized controlled trials found no consistent evidence that postmenopausal estrogen alone or in combination with a progestin promotes or prevents weight gain. These results contrast with the 3-year PEPI trial results, where women within 10 years of menopause who were assigned to HT (estrogen with or without one of three progestational agents) had, on average, 1.0-kg less weight gain and 1.2-cm less increase in waist girth than women assigned to placebo (24). Similarly, WHI women assigned to EPT reduced weight by 0.4% and waist circumference by 0.9% from baseline to year 1, compared with placebo (59). Urogenital Symptoms and Sexual Function GENITAL COMPLAINTS After menopause, the urogenital mucosa becomes thinner, less elastic, and less vascular. The vagina shortens and narrows, developing a thin, friable surface, generally called vaginal atrophy. Vulvovaginal symptoms, which do not necessarily parallel clinical findings, include dryness, pruritis, discharge, dyspareunia, and postcoital bleeding. Nevertheless, older women often report a satisfactory sex life without HT. In the Massachusetts Women s Health Study (8), factors such as marital status and sexual dysfunction of partner, physical and mental health, and cigarette smoking had a greater impact on sexual functioning than menopause status. Studies of symptomatic women generally suggest that HT improves genital symptoms and sexuality, but there are no quantitative reviews and diverse definitions of sexual function impede synthesis (9). In WHI-EPT, active treatment of older women had no effect on sexual satisfaction as assessed by a 4-point response scale (40). VAGINAL DRYNESS A meta-analysis of 10 randomized, controlled clinical trials showed that oral, transdermal, and intravaginal ET (cream, tablet, or vaginal ring) reduced vaginal symptoms among women with vaginal dryness or dyspareunia (19). In HERS, 61% of women assigned to oral EPT and 47% assigned to placebo reported improvement in genital dryness (11). Although there are few head-tohead comparisons, vaginal application seems to provide superior relief compared with systemic ET and raises circulating estrogen concentrations less than oral ET, which may improve the safety profile. LIBIDO There is no evidence that reduced sexual desire beginning during the menopause transition is caused by estrogen deficiency or improved by ET. The reverse is plausible because oral estrogen increases sex hormone-binding globulin, which reduces bioavailable testosterone and estradiol (83). This effect on sex hormone binding globulin may explain why estrogen plus testosterone improved sexual enjoyment, desire, and arousal more than estrogen alone in two clinical trials (57, 76).

7 MENOPAUSAL HORMONE THERAPY 121 URINARY COMPLAINTS Urinary tract symptoms previously attributed to estrogen deficiency include dysuria, frequency, nocturia, urinary incontinence, and urinary tract infection. Of these, only the frequency of recurrent urinary tract infection has been shown in clinical trials to be reduced by estrogen treatment (23, 71). However, HT did not prevent urinary tract infections in HERS women without prior urinary tract infections (17). No good evidence supports the notion that HT improves or protects against stress or urge incontinence. In the HERS trial, women with incontinence at baseline who were treated with EPT reported worsened incontinence compared with those treated with placebo; similarly, women without incontinence at baseline were more likely to develop incontinence when assigned to EPT (29). HORMONE THERAPY TO PREVENT CHRONIC DISEASE The potential of ET to prevent diverse conditions that are common in later life was a major impetus for long-term HT. Observational studies reported that women using HT had fewer fractures, less heart disease, less colon cancer, and less dementia, but a healthy-user bias could explain some or all of these putative benefits. For example, women physicians in Britain who continued HT were more likely than non-hormone-using physicians to report a healthy diet and vigorous physical activity (51). In a U.S. prospective study, women who elected to use HT after menopause were healthier before menopause than those who did not choose to use HT (60). Only randomized, placebo-controlled clinical trials, the basis of evidence-based medicine, can control for the effects of known and unknown differences between postmenopausal women who do or do not take hormones. Nowhere has the importance of clinical trials been so evident as in the past five years, when the results of HT trials have contradicted several of the findings of earlier observational studies of HT. Table 1 shows characteristics of the participants, the intervention, and the duration for the three large chronic disease outcome trials: HERS and the two WHI hormone trials. Table 2 summarizes the results from these trials with regard to major clinical outcomes. Figure 2 shows the absolute risks in rates per 10,000 women per year from WHI-EPT and WHI-ET. When comparing and contrasting WHI- EPT and WHI-ET results, it is important to understand that these are two different trials, not only with regard to treatment, size, and duration (See Table 1), but also because the trial cohorts are quite different. To be eligible for WHI-ET, women were required to have had a hysterectomy, and more than 40% reported a bilateral oophorectomy. In addition, a substantially greater percentage of WHI-ET women had used HT in the past, and on average they had first births at younger ages and had had more live births than had WHI-EPT participants. WHI-ET women were also more overweight and had more hypertension and diabetes at baseline than did women in WHI-EPT. Furthermore, the percentage of minority women was

8 122 BARRETT-CONNOR GRADY STEFANICK TABLE 1 Characteristics of three hormone therapy outcome trials Trial N Study drug (mg/d) Eligibility criteria Primary outcomes Duration (years) HERS 2763 CEE Heart disease Heart disease 4.1 MPA 2.5 No hysterectomy WHI-EPT 16,608 CEE No hysterectomy Heart disease 5.2 MPA 2.5 Breast cancer Global index WHI-ET 10,739 CEE Hysterectomy Heart disease 6.8 Breast cancer Global index TABLE 2 substantially greater in the WHI-ET, particularly for African American women (89). WHI-EPT results were first published in More detailed subsequent reports from WHI-EPT have been published for most of the major outcomes, which include somewhat longer follow-up (5.6 vs. 5.2 years), additional cases, and central adjudication of outcomes that was not available at the time of the first publication. This has not materially changed the results, but small differences may confuse the Clinical event Hazard ratios from three hormone therapy trials HERS (estrogen + progestin) (49, 82) Hazard ratio (95% confidence interval) WHI (estrogen + progestin) (75) WHI (estrogen) (6) CHD events 0.99 ( ) 1.29 ( ) 0.91 ( ) Stroke 1.23 ( ) 1.41 ( ) 1.39 ( ) Pulmonary embolism 2.79 ( ) 2.13 ( ) 1.34 ( ) Breast cancer 1.30 ( ) 1.26 ( ) 0.77 ( ) Colon cancer 0.69 ( ) 0.63 ( ) 1.08 ( ) Hip fracture 1.10 ( ) 0.66 ( ) 0.61 ( ) Death 1.08 ( ) 0.98 ( ) 1.04 ( ) Global index 1.15 ( ) 1.01 ( ) Abbreviations: CHD, coronary heart disease; HERS, Heart and Estrogen/Progestin Replacement Study; WHI, Women s Health Initiative;, not calculated. These data are from the initial WHI reports for EPT and CEE and differ slightly from subsequent updated reports presented in this review. Data are based on the intent-to-treat analyses. For the primary CHD events outcome (myocardial infarction plus CHD death), the three trials had similar numbers of events and thus similar power. For other outcomes the smaller HERS trial had fewer events and less-precise hazard ratios. The global index was composed of the first occurrence of any of the events listed in the table. Permission to reprint from Hulley SB, Grady D The WHI Estrogen-Alone Trial Do things look any better? JAMA 291: (48a, table 1, p. 1770). Copyright c 2004 American Medical Association. All rights reserved.

9 MENOPAUSAL HORMONE THERAPY 123 Figure 2 Clinical outcomes by randomization assignment (N per 10,000 per year) for the Women s Health Initiative Estrogen plus Progestin (upper panel) and Estrogen alone (lower panel) trials. unwary reader. The second papers on each of the seven primary outcomes include stratified analyses and tests for interaction, seeking subgroups of women for whom HT might show particular risk or benefit. Another cautionary note about the WHI trials is that both the percentage of women who stopped taking study pills ( drop-out ) and the percentage who initiated active hormone therapy through their personal health care providers ( dropin ) exceeded design projections within the first year in both active and placebo arms and steadily increased over the course of the trials; in addition, although some women resumed study pills at some point, only cumulative drop-in and drop-out rates were reported. At the time the WHI-EPT trial was stopped, i.e., after an average of 5.2 years of follow-up, the cumulative drop-out rates were 42% for EPT and 38% for placebo, and the cumulative drop-in rates were 6.2% for EPT and 10.7% for placebo. At the time the WHI-ET trial was terminated, i.e., after an average of 6.8 years of follow-up, cumulative drop-out rates were 54% for both ET and placebo and drop-in rates were 5.7% for ET and 9.1% for placebo. Nonadherence can spuriously reduce the true benefit and the true harm of treatment.

10 124 BARRETT-CONNOR GRADY STEFANICK Osteoporosis and Fractures BONE DENSITY AND BONE LOSS The balance between bone formation and bone resorption is disturbed during the menopause transition, before menses cease, when follicle-stimulating hormone (FSH) levels are high but estrogen levels are relatively normal. Bone loss is often, but not always, accelerated for several years after menopause, averaging 2% per year (range <1% 5%), after which there is a steady slow bone loss of about 0.5% per year. Some women show little change in bone mineral density after menopause (37). In very old age, bone loss may accelerate again, probably related to immobility, intercurrent illness, poor nutrition, or secondary hyperparathyroidism. Fracture risk increases with age and is closely related to bone density, bone connectivity, body size, balance, strength, and the propensity to fall. In the United States, a 50-year-old white woman has a 15% lifetime risk of hip fracture, usually occurring after age 70, a 40% risk of at least one spine fracture, and a 15% risk of wrist fracture, the latter two generally occurring before age 60 (72). Long before the estrogen-prevents-heart-disease hypothesis prompted widespread use of HT, the prevention of osteoporosis and fractures was the main indication for HT in women not seeking therapy for menopause symptoms. Many clinical trials have shown that estrogen therapy increases bone density in postmenopausal women, whether therapy began at menopause or in old age. A systematic review and meta-analysis that included results of 57 randomized, placebo-controlled clinical trials published between 1966 and 1999 reported a statistically significant increase in bone density in favor of HT (97). After one year, the change in bone density was 5.4% better at the lumbar spine, 3.0% better at the forearm, and 2.5% better at the femoral neck compared with placebo. After two years of treatment the percent change favoring HT increased further by about 1.5% at each site. At the end of two years, there was a significant dose-response effect with better bone density at the hip and spine in women taking higher doses of HT (0.9 mg) than lower doses (0.3 mg). HT also increased bone mineral density (BMD) at the hip and spine in the PEPI trial (37), with no significant differences between the bone effects of ET alone or given with any of three progestational regimens. Low doses may be adequate to maintain bone, however. In one small, randomized, placebo-controlled trial, an ultralow dose (0.25 mg/d) of oral micronized 17 beta-estradiol increased bone density at the hip and spine (69). In another larger randomized trial, 14 µg oftransdermal estradiol per day increased bone density at the spine and hip compared with placebo (25). HT must be continued to maintain the bone sparing effect (27). On the basis of data from the large National Osteoporosis Risk Assessment (NORA) observational study, women who used HT for 5 10 years after menopause and then quit had no better bone density at the radius or heel at age 70 than did women who had never used HT (14). Recency of use was much more important than duration of use, compatible with the observation that bone loss accelerates when HT is discontinued.

11 MENOPAUSAL HORMONE THERAPY 125 FRACTURE In a large observational study of more than 138,737 postmenopausal English women followed for an average of 2.8 years, current HT was associated with a significantly reduced risk of fracture (RR 0.62, 95% CI ), and the benefit was similar for ET and EPT (10). Fracture incidence rates returned to those of never-users about one year after discontinuing HT (10). Until recently the best trial evidence that HT prevents fractures came from systematic reviews of small clinical trials. A review of 22 small trials reported a 27% summary relative risk reduction in nonvertebral fractures (90). A metaanalysis of the results of 7 clinical trials of HT with fracture outcomes (5 vertebral and 6 nonvertebral) found a 34% summary relative risk reduction for vertebral fractures and a 13% reduction for nonspine fractures; in neither case were the differences statistically significant (97). WHI-EPT was the first trial large enough to unequivocally show that HT prevents fractures, even in women unselected for osteoporosis (75). Less than 6% of WHI-EPT women probably had osteoporosis, on the basis of BMD measured in 1024 women at 3 of the 40 WHI sites. About 5 years of combined continuous EPT reduced the risk of all fractures by 24% and the risk of hip fractures by 33% compared with placebo (see Table 2, Figure 2). Overall, 733 (8.6%) women in the EPT arm and 896 women (11.1%) in the placebo group had a fracture during the average 5.6-year follow-up (20). The effect of HT on fracture risk did not differ significantly by age, time since menopause, body mass index, smoking, personal or family history of fracture, past use of HT, or bone density. Even in the highest fracture risk group, the reduced hip fracture benefit did not exceed the other harms of HT (20). In subset analyses of WHI-EPT, there was only one statistically significant interaction: a 60% greater reduction in risk of hip fracture among women who reported a baseline dietary calcium intake of more than 1200 mg/day, compared with women who reported less calcium intake. This finding is compatible with the results of observational studies that consistently show better bone preservation in women who take both estrogen and calcium (65). The unopposed estrogen arm of the WHI showed a similar statistically significant reduction in fracture risk with ET versus placebo in 10,739 women who were followed for an average of 6.8 years (6). In WHI-ET, the risk of hip fracture was reduced by 39% and the risk of clinical spine fracture was reduced by 38%. Coronary Heart Disease Coronary heart disease is the leading cause of death in women in most of the westernized world. Enthusiasm for nearly universal use of HT stemmed from observations that the risk might be reduced by as much as 50%, and this apparent protection would outweigh any other potential risks (32). Although a plethora of putative cardioprotective mechanisms were observed (including favorable changes in LDL and HDL cholesterol, Lp(a), vasoreactivity, fibrinogen, fasting blood glucose, homocysteine, and nitric oxide), the most persuasive evidence came from more than thirty epidemiologic studies that suggested a 30% 50% reduced risk of

12 126 BARRETT-CONNOR GRADY STEFANICK heart disease in women using estrogen compared with nonusers (13, 32). On the basis of this evidence, estrogen was promoted for the prevention of heart disease. A recent meta-analysis restricted to 18 good quality observational studies reported similar cardiac protection, but this apparent benefit disappeared when the analysis was restricted to the few observational studies that controlled for socioeconomic status, for alcohol consumption and physical activity, or both (50). The first clinical trial evidence that HT might not prevent coronary heart disease in postmenopausal women came from a 1997 systematic review of 22 small, short, clinical trials performed to test the effect of HT on a variety of outcomes. Myocardial infarction and coronary death were not primary outcomes but were collected as adverse events or reasons for discontinuation. The summary results of these trials showed an increased cardiovascular risk in women assigned to HT (42). Published in 1998, HERS was the first large, placebo-controlled clinical trial of EPT with coronary heart disease as the primary outcome (49). The 2763 HERS participants, all of whom had documented heart disease at baseline and an intact uterus (necessary for the test of efficacy of combined hormone therapy), experienced a 50% increased risk of coronary events during the first year and no overall reduction in the risk of fatal and nonfatal coronary disease or stroke after 4 years. A 3-year extension of HERS showed no evidence of later protection (relative hazard after 6.8 years of follow-up 1.00; 95% CI ) (31). An extensive search for subgroups of women who might have been helped or harmed in HERS produced no convincing explanation for the early harm or overall absent benefit (26). Two of the most popular explanations for this unexpected result were that HT could not decrease the risk of cardiovascular events in women who already had coronary artery atherosclerosis or that the progestin offset the benefit of estrogen. In July 2002, the 16,608 WHI-EPT participants were informed that the trial was being stopped 3.3 years early because an increased risk of breast cancer crossed a preestablished stopping boundary and was accompanied by an overall balance of harm greater than benefit with respect to 8 prespecified outcomes. As shown in Table 2, there was a 29% increased risk of coronary heart disease, a 41% increased stroke risk, and a 113% increased risk of pulmonary embolism (75). The increased risk of myocardial infarction and venous clotting in the hormone group was apparent in the first year of the trial, whereas the increased stroke risk was not seen until after the first year. Figure 2 shows that the number of additional cases of vascular disease attributed to EPT exposure (above rates in the placebo group) was small but greater than the number of other conditions prevented. In an updated report, the hazard ratio for CHD was 1.24 (CI ) (59). There was a higher relative risk for coronary events associated with EPT among women with high LDL-cholesterol compared with those with low baseline LDL-cholesterol. However, this subgroup finding was one of more than 20 subgroup analyses performed and may have occurred by chance. There was no interaction of treatment effect with age, years since menopause, C-reactive protein, or other biomarkers. EPT had no effect on rates of revascularization procedures, confirmed angina, acute coronary syndrome, or congestive heart failure (59).

13 MENOPAUSAL HORMONE THERAPY 127 Stroke WHI-ET, the estrogen-only trial with 10,739 women enrolled, was stopped 2 years prematurely in 2004, after an average of 6.6 years (6). The main reason for stopping this trial early was a 39% increased incidence of stroke among ET users and a very low likelihood for future cardiac benefit. The fact that there was no overall benefit and the improbability of showing a more favorable balance of benefits and risks by continuing the trial were also considerations in stopping the trial (Table 2). Women in WHI-ET assigned to unopposed estrogen, unlike women in HERS and WHI trials of combined therapy, experienced no early excess risk of coronary events. Similar to the previous trials, there was also no reduction in risk of coronary events during the trial (Table 2 and Figure 2). As shown in Figure 2, the risk of heart disease among women assigned to placebo was higher in WHI- ET than in WHI-EPT, possibly owing to greater baseline risk for heart disease [i.e., more obesity, hypertension, diabetes, or prior heart disease, which may be associated with hysterectomy or factors leading to the hysterectomy (59)]. Several other smaller randomized trials, some using unopposed oral or transdermal estradiol, also found no protection against coronary artery disease (12). Thus, there is no evidence that HT with or without a progestin prevents coronary heart disease. The null results with unopposed ET should lay to rest the notion that the use of a progestin explains the lack of cardioprotection in HERS and WHI-EPT but leaves open the possibility that the early harm observed in HERS and WHI-EPT was related to daily use of medroxyprogesterone. However, women enrolled in WHI-EPT and -ET were sufficiently different that the small differences in early harm between the trials cannot be attributed necessarily to the presence or absence of a progestin. A meta-analysis of 9 observational studies among women with no history of stroke showed a small but significant increased risk of stroke associated with hormone use (relative risk 1.12; 95% CI ) (4). The risk of stroke in the 2763 women in the HERS trial, who all had documented coronary artery disease, was increased but not significantly so (hazard ratio 1.23; 95% CI ; Table 2) (82). In the Women s Estrogen for Stroke Trial (WEST) (94), 664 women who had a history of stroke or transient ischemic attack at enrollment were randomly assigned to unopposed 17 beta-estradiol or placebo and followed for an average of 2.8 years. Women assigned to ET experienced a nearly threefold increased risk of fatal stroke (RR 2.9; 95% CI ). There was no excess risk of nonfatal stroke in the ET group, but the stroke survivors had slightly worse neurologic or functional deficits. The first trial evidence of a statistically significant excess risk of stroke with HT came from the WHI trials (6, 75), with a hazard ratio of 1.41 for combined therapy in WHI-EPT and 1.39 for unopposed estrogen in WHI-ET (Table 2). In

14 128 BARRETT-CONNOR GRADY STEFANICK an updated report, the hazard ratio for total stroke was 1.31 (CI ); the authors suggested that the risk was likely underestimated owing to the relatively low adherence rates in WHI: In an analysis restricted to women who were adherent to study medication, the hazard ratio increased to 1.50 (95% CI ) (95). The increased risk with EPT was predominantly for ischemic stroke (HR 1.44; 95% CI ) and was similar across all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, or use of statins or aspirin. In WHI-ET, stroke was the only statistically significant adverse event attributable to unopposed estrogen. As shown in Figure 2, WHI-ET women assigned to ET experienced 12 additional stroke events per 10,000 treated women per year. In age-specific analyses, the hazard ratio was highest among women aged (1.65; 95% CI ). There were very few strokes in women younger than age 60. Breast Cancer Breast cancer accounts for 32% of new cancers diagnosed in women each year and is second only to lung cancer as the leading cause of cancer death in U.S. women (15% versus 25%). Breast cancer risk is related to endogenous estrogen, as shown in a pooled analysis of 9 prospective studies of postmenopausal women. in which a doubling of estradiol levels was associated with a 23% 35% increased risk of breast cancer with no evidence of a threshold effect (3). The results of early observational studies of the association of HT and breast cancer were inconsistent, likely reflecting failure to consider duration of HT use and the role of obesity, reproductive history, and oophorectomy. A pooled reanalysis of data from 51of 63 published observational studies of HT and breast cancer, which included 52,705 women with breast cancer and 108,411 without breast cancer, showed an increased risk of breast cancer that was clearly evident after 5 years of ET (2). Breast cancer risk increased 2.3% for each year of use beyond 5 years, the same as the increased risk for each year of delayed menopause, providing internal consistency to the thesis that estrogen promotes breast cancer. In women who used HT for more than 5 years, the increased risk of breast cancer was slightly but not significantly higher in women using EPT (OR = 1.53) than those using ET alone (OR 1.34); only 12% reported using EPT. Most of the observational studies included in this large pooling project were from the United States, where women who use HT are more likely than women who do not use HT to have frequent mammograms making diagnostic detection bias a possible explanation for any observed excess breast cancer risk. The Million Women Study, an observational study that included 828,923 postmenopausal British women who had breast cancer screening every third year, largely excludes diagnostic detection bias (15). After 2.6 years of follow-up, women who were current HT users at baseline were significantly more likely to develop breast cancer. The relative risk of breast cancer in women taking EPT

15 MENOPAUSAL HORMONE THERAPY 129 (the predominant progestin was norgestrel or levonorgestrel) was higher than the relative risk in women taking unopposed ET (relative risk 2.0; 95% CI vs. 1.30; 95% CI ). Results were similar for oral, transdermal, or implanted estrogen, and varied little by specific estrogens or progestins or their doses. In an analysis combining women who were current users of ET or EPT, the HT treated women were more likely to have fatal breast cancer. Despite the strong epidemiologic evidence that estrogen is a cause of breast cancer, WHI was the first clinical trial of sufficient size and duration to test this hypothesis. In WHI-EPT, a 26% increased risk of invasive breast cancer (95% CI ) was first apparent after 4 years of combined HT, with a calculated absolute excess risk of 8 more invasive breast cancers per 10,000 persons per year attributable to estrogen plus progestin (Table 2 and Figure 2) (75). In an updated report, the hazard ratio was 1.24 (CI ) (21). This increased relative risk is similar to the (nonsignificantly) increased risk observed in the smaller HERS study (hazard ratio 1.30; Table 2). Contrary to expectations, the invasive breast cancers observed in WHI-EPT women assigned to EPT were significantly larger and at a more advanced stage than breast cancers observed in women assigned to placebo (21). In contrast, no significant increase in risk of breast cancer was found in women assigned to unopposed conjugated estrogen in WHI-ET (6). In fact, there was a trend to reduced breast cancer risk among women assigned to the estrogen group (relative risk 0.77; P = 0.06). This pattern of decreased risk of breast cancer differs from the findings of prior observational studies and clinical trials and could be due to chance. Despite previously described relevant differences in body mass index and parity between the WHI-ET and -EPT cohorts, the annualized rates for breast cancer were very similar in the placebo groups for the two trials. Future analyses from the WHI-ET, including information regarding the tumor characteristics, may clarify this situation. The higher risk of breast cancer observed in WHI-EPT but not in WHI-ET may be due to the progestin, concordant with the results in the Million Women Study (15). Higher breast density is a strong risk factor for breast cancer in postmenopausal women (16). Evidence for a true difference between ET and EPT comes from the breast density changes observed in PEPI, showing that EPT increases breast density more than treatment with estrogen alone. In the PEPI trial of 875 relatively young postmenopausal women, no women taking placebo showed increased mammographic parenchymal density after one year while 16.4% 23.5% women taking an estrogen-plus-progestin regimen developed increased breast density, compared with only 3.5% of women taking unopposed estrogen (36). After one year in WHI- EPT, nearly twice as many women assigned to EPT had abnormal mammograms compared with placebo (21). Similar data are not yet available for WHI-ET. Women with breast cancer who were surgically or chemically castrated before the age of natural menopause often experience severe menopause symptoms. The Hormonal Replacement Therapy after Breast Cancer (HABITS) trial was designed to determine whether ET is safe for the treatment of menopause symptoms in

16 130 BARRETT-CONNOR GRADY STEFANICK relatively young (mean age 55) breast cancer survivors (46). Eligible women had less than four positive lymph nodes and were free of breast cancer recurrence. The specific HT regimen used was chosen by the patient s physician. This trial was stopped early, after two years, because there was a significant excess of breast cancer in women assigned to HT compared with placebo (RH 3.5; 95% CI ). The risk was highest in women who had used ET prior to the diagnosis of breast cancer and in women with estrogen-receptor-positive breast cancers (47). A concurrent trial in Stockholm that had previously planned to pool results with HABITS was also stopped early on the basis of recruiting difficulties and the HABITS results. Endometrial Cancer Endometrial cancer, the most common gynecological cancer in women, was the first cancer to be definitely associated with ET. In a 1995 meta-analysis of the results from 29 observational studies (30), 5 years of unopposed estrogen increased the endometrial cancer risk four- to fivefold, and 10 years of use increased risk approximately tenfold; overall there was a two- to threefold increased risk (95% CI ) in women who used unopposed ET. The summary risk for fatal endometrial cancer after 5 or more years of ET in 4 observational studies was 2.7 (95% CI ). A meta-analysis of 6 observational studies and 1 trial that evaluated EPT found no increased risk of endometrial cancer (RR 0.8; 95% CI ) (30). In another review, EPT with continuous combined or cyclic progestin used for 10 or more days per cycle carried no increased risk (7). In a more recent prospective observational study, treatment with up to 5 years of continuous combined estradiol (2 mg) plus norethisterone (1 mg) daily was not associated with endometrial hyperplasia, and preexisting hyperplasia reverted to normal in HT-treated women (98). Endometrial hyperplasia, particularly atypical hyperplasia, is a precursor for endometrial cancer, and prevention of hyperplasia prevents endometrial cancer (63). The best clinical trial evidence is from the PEPI trial, which found that using daily estrogen plus a progestin for days each month or daily estrogen plus daily progestin prevents endometrial hyperplasia, and presumably endometrial cancer (1). In PEPI women, unopposed estrogen increased the risk of endometrial hyperplasia by 10% per year (1). These endometrial changes were not observed in women taking CEE plus continuous or cyclic MPA or cyclic micronized progesterone. Both HERS and WHI-EPT confirmed that the risk of endometrial cancer was not increased among women assigned to EPT compared with placebo (relative risk in HERS 0.25; 95% CI ; relative risk in WHI-EPT 0.81; 95% CI ) (5, 48). These results indicate that progestin prevents the increased risk of endometrial cancer associated with unopposed ET. More recent trials with low-dose unopposed ET show very low rates of endometrial hyperplasia, which suggests that a smaller dose of progestin (93), or perhaps no added progestin (25), will be required to prevent endometrial hyperplasia and cancer.

17 MENOPAUSAL HORMONE THERAPY 131 Colon Cancer Colorectal cancer is the third most common cancer in women in the United States. In a systematic review of 21 published observational studies of HT and colorectal cancer, 9 reported a significant reduction in colorectal cancer, 9 reported no significant protective effect, and 3 reported a small nonsignificant increased risk (41). Another meta-analysis restricted to 18 studies that met specific inclusion criteria found a significantly reduced risk of colon cancer that was greater among current users (38). WHI-EPT demonstrated a 44% reduced risk of invasive colon cancer in women assigned to EPT compared with placebo (0.56: 95% CI ), with an absolute risk reduction of 6 fewer colorectal cancers per 10,000 women per year (22, 75). There was a similar reduced risk of colon and rectal cancer. More than 20 subgroups were tested for interactions with no significant differences found. Although there were fewer colorectal cancers, the authors reported that WHI women in the EPT group had a significantly greater number of positive lymph nodes and a more advanced stage at diagnosis (22). In contrast with the reduced risk of colon cancer observed among women in WHI-EPT, colon cancer diagnoses were not reduced among women assigned to unopposed estrogen in WHI-ET (HR 1.08; 95% CI ) (6). Although the numbers were too small for definitive interpretation, there was a suggestion of reduced colon cancer risk in HERS after 6.8 years of follow-up (RR 0.69; 95% CI ) (48). Given the inconsistency of observational studies and the trial results, it is impossible at this point to conclude that EPT prevents colon cancer. Ovarian Cancer Ovarian cancer is the most lethal gynecologic cancer. It is relatively uncommon (4% of new cancers in women; 6% of annual cancer deaths) but not rare, diagnosed in 1 in every 57 U.S. women. Although some case-control studies reported an excess risk of ovarian cancer in women taking EPT or unopposed estrogen (55, 73, 74), most found no association. In a meta-analysis of ten observational studies, use of HT was associated with an increased risk of invasive epithelial ovarian cancer (OR 1.14; 95% CI ); the risk was highest in women who had used HT for more than 10 years (28). In a more recently reported U.S. cohort study, estrogen alone, but not EPT, was associated with a significantly increased risk of ovarian cancer (55). A Swedish study reported an increased risk of ovarian cancer after ET and sequential EPT (OR 1.43; 95% CI , and OR 1.54; 95% CI , respectively) but found no increased risk after continuous combined EPT (73). Death rates in a very large U.S. prospective study found that women using HT at baseline (presumably primarily unopposed estrogen) had a significantly increased risk (RR 1.51; 95% CI ) compared with nonusers, with a similar risk in former users of 10 or more years duration (74). Risk decreased with time since last use. In the only published clinical trial, the WHI-EPT trial (5), women assigned to EPT had a 58% increased risk for ovarian cancer compared with placebo (1.58; 95%

18 132 BARRETT-CONNOR GRADY STEFANICK CI ), a difference that was not statistically significant. In WHI-EPT there were no differences in histological grade, state, or interactions by race/ethnicity, body mass index, family history of breast or ovarian cancer, or prior oral contraceptive or HT use. Cognition and Dementia Memory loss, cognitive dysfunction, and dementia are some of the most feared complications of aging. Many observational studies suggested that ET could improve postmenopausal memory loss or prevent dementia, and several short clinical trials in recently oophorectomized women showed improved verbal memory (79). A systematic review of the results of 12 clinical trials (56) found a significantly reduced relative risk of developing dementia in healthy women taking estrogen, but there was substantial heterogeneity in the results. A meta-analysis of 5 trials including 210 women with dementia found a clinically nonsignificant improvement in cognitive function scores among women treated with mg of CEE (but not higher doses), and only for the first few months (45). After correcting for multiple testing, only a short-term improvement in memory remained among women treated with ET, compared with those treated with placebo. Other clinical trials have not confirmed these benefits. No benefit of treatment with estrogen was shown in a one-year clinical trial in which 120 women with early Alzheimer s dementia were randomly assigned to placebo or unopposed CEE (either mg or 1.25 mg) (64). In this trial, scores on the clinical dementia rating scale were actually significantly worse in women assigned to estrogen compared with the results in women assigned to placebo. At the end of HERS, approximately 1000 older women with heart disease completed 6 standard cognitive function tests; women assigned to HT did not perform better on any test than did women assigned to placebo (34). In the Women s Health Initiative Memory Study (WHIMS), 7479 women aged 65 and older who were participating in the WHI-EPT (N = 4532) or -ET (N = 2947) trials (i.e., more than 92% of age-eligible WHI-HT participants) completed the Modified Mini-Mental State Examination (3MSE). When the WHI-EPT was stopped, after an average of 4.1 years of WHIMS EPT follow-up, more women in the EPT group had a substantial [ 2 standard deviations (SD)] decline in 3MSE total score than did women in the placebo group (6.7% vs. 4.8%, P = 0.008) (70). After an average of 5.2 years of WHIMS follow-up when the WHI-ET was stopped, 3MSE scores averaged 0.26 units lower among ET women compared with placebo (P = 0.04), and the odds of 2 SDs decline in 3MSE scores was increased by 50% (this was not significant) (70). For pooled EPT and ET, the mean decrement on the 3MSE was 0.21 among women treated with HT compared with placebo (P = 0.005). Findings were similar among subgroups classified by prior use of HT, age, and markers of socioeconomic status and health. The adverse impact of either HT regimen was more pronounced among women with lower cognitive function at baseline (70). The risk of probable dementia in WHI women assigned to EPT was increased twofold (HR 2.05; 95% CI ) (81). In the 2947 WHIMS women from WHI-ET, the incidence of probable dementia following ET was increased

19 MENOPAUSAL HORMONE THERAPY 133 by 49% (HR % CI ) (80). This increased risk does not differ significantly from that observed with EPT; for pooled WHIMS data from WHI- EPT and WHI-ET the overall hazard ratio was 1.76 (95% CI ) (80). The authors suggest that the higher risk of dementia in women assigned to ET or EPT could be due to micro infarcts or other vascular brain disease, consistent with the increased risk of stroke in both trials. Venous Thromboembolic Disease Oral contraceptives increase the risk of venous thromboembolic events (VTE) including deep vein thrombosis and pulmonary emboli, but the association of VTE with the lower-dose estrogen regimens used in postmenopausal women has been controversial. There is now little doubt that VTE is a complication of HT. A meta-analysis of 12 studies (including 3 trials) found a summary relative risk of 2.14 (95% CI ) for VTE among HT users compared with nonusers, or 1.5 excess cases per 10,000 women per year of use (61). However, these studies included only idiopathic venous thromboembolic events, and excluded high-risk women. The excess rate of any VTE in unselected HT users is likely higher. On the basis of population rates of 34 per 10,000 in women more than 50 years old and 42 per 10,000 in women more than 60 years old (67), excess risk likely ranges from 6 12 per 1000 HT users per year. In the older women in the HERS trial, the absolute risk was high, 1 per 250 users per year (even though many HERS women were taking aspirin and statins, medications that may reduce the risk of venous thromboembolism) (33). Compatible with observational studies (39), the risk for VTE among HERS women assigned to EPT was highest in the first two years of treatment (three- to fourfold higher than placebo), decreased over the next three years, and was not different from placebo by the fifth year of follow-up (48). Among the generally healthy women enrolled in WHI-EPT, EPT approximately doubled the risk of VTE (RH 2.11; CI: ) (75). The relative risk was greatest in the first year but was still apparent after 4 5 years of treatment. In WHI-ET, women in the ET group had a smaller, nonsignificant increase in risk for VTE (relative risk 1.33; 95% CI ) versus placebo. The apparent difference between EPT and ET in the WHI is not statistically significant. The mechanism whereby HT causes VTE is not clear, but it may be related to changes in coagulation factors that are the result of liver metabolism of oral estrogen. If this is true, transdermal estrogens, which avoid first-pass liver metabolism, might avoid the increase in risk of VTE associated with oral estrogens. Some observational data support this hypothesis (77), but there are no clinical trials large enough to provide definitive data. Global Index WHI investigators constructed a global index for eight clinically significant disease outcomes (coronary disease events, stroke, hip fracture, pulmonary embolism, breast, colon, and endometrial cancer, and death from other causes). Figure 2 shows the global index for the treatment groups in WHI-EPT and ET. In the WHI-EPT

20 134 BARRETT-CONNOR GRADY STEFANICK analysis, small risks exceeded the small benefits of combined therapy. In WHI-ET, the small benefits of unopposed estrogen equal the small risks. Other trials with other regimens, routes, and doses are beginning, although none apparently is large enough to examine clinical cardiovascular events or cancer. Such regimens may be safer or more dangerous. CONCLUSIONS Despite the apparent ubiquity of estrogen receptors in diverse human tissues, and estrogen s multiple biologic effects, clear randomized, clinical trial evidence of benefit for systemic HT is presently limited to relief of vasomotor and vaginal symptoms. For longer use, HT prevents bone loss and fractures but also increases the risk of other life-threatening events resulting in no overall benefit. On the basis of WHI-EPT and WHI-ET, the risks for combined or unopposed therapy are an increased risk of stroke that does not decrease with time, an increased risk of VTE that may wane over time, and, in older women, an increased risk of dementia. None of these trials excludes the possibility that other doses, routes, or regimens would have a better risk-benefit ratio for the prevention of disease. The two areas of greatest current interest, with clinical trials in development, are the possibility that younger women may have a better risk-benefit ratio than older women and the possibility that the bone benefits of HT could be maintained at much lower doses, possibly below the threshold for causing stroke, breast cancer, and other untoward effects. These trials have mainly intermediate outcomes such as bone density and atherosclerosis but could serve as pilot tests for trials with clinical outcomes if the results suggest benefit greater than harm. Meanwhile, it seems that the title of this chapter is also a work in progress. To quote from a financial forecasting document used by industry, a Women s Reproductive Health 2004 report received via on April 7, 2004, Negative press regarding the side-effects associated with hormone replacement therapy (HRT) has slowed this market down slightly, leaving a vacuum of market share for other osteoporosis therapies. HRT will, however, rebound during the forecast period and reachieve strong growth (Y. Sule, personal communication). One hopes also for improved understanding. The Annual Review of Public Health is online at LITERATURE CITED Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 275: Breast cancer and hormone replacement therapy: collaborative reanalysis of

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22 136 BARRETT-CONNOR GRADY STEFANICK estrogen plus progestin on risk of fracture and bone mineral density: the Women s Health Initiative randomized trial. JAMA 290: Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, et al Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women s Health Initiative Randomized Trial. JAMA 289: Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J, et al Estrogen plus progestin and colorectal cancer in postmenopausal women. N. Engl. J. Med. 350: Eriksen B A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am. J. Obstet. Gynecol. 180: Espeland MA, Stefanick ML, Kritz- Silverstein D, Fineberg SE, Waclawiw MA, et al Effect of postmenopausal hormone therapy on body weight and waist and hip girths. Postmenopausal Estrogen-Progestin Interventions Study Investigators. J. Clin. Endocrinol. Metab. 82: Ettinger B, Ensrud KE, Wallace R, Johnson KC, Cummings SR, et al Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet. Gynecol. 1104: Furberg CD, Vittinghoff E, Davidson M, Herrington DM, Simon JA, et al Subgroup interactions in the Heart and Estrogen/Progestin Replacement Study: lessons learned. Circulation 105: Gallagher JC, Rapuri PB, Haynatzki G, Detter JR Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers. J. Clin. Endocrinol. Metab. 87: Garg PP, Kerlikowske K, Subak L, Grady D Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet. Gynecol. 92: Grady D, Brown JS, Vittinghoff E, Applegate W, Varner E, Snyder T Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet. Gynecol. 97: Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet. Gynecol. 85: Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, et al Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA 288: Grady D, Rubin SM, Petitti DB, Fox CS, Black D, et al Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann. Intern. Med. 117: Grady D, Wenger NK, Herrington D, Khan S, Furberg C, et al Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/Progestin Replacement Study. Ann. Intern. Med. 132: Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/Progestin Replacement Study. Am. J. Med. 113: Greendale GA, Reboussin BA, Hogan P, Barnabei VM, Shumaker S, et al Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/ Progestin Interventions Trial. Obstet. Gynecol. 92: Greendale GA, Reboussin BA, Sie A, Singh HR, Olson LK, et al

23 MENOPAUSAL HORMONE THERAPY 137 Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators. Ann. Intern. Med. 130: Greendale GA, Wells B, Marcus R, Barrett-Connor E How many women lose bone mineral density while taking hormone replacement therapy? Results from the Postmenopausal Estrogen/Progestin Interventions Trial. Arch. Intern. Med. 160: Grodstein F, Newcomb PA, Stampfer MJ Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am. J. Med. 106: Gutthann SP, Garcia Rodriguez LA, Raiford DS Individual nonsteroidal antiinflammatory drugs and other risk factors for upper gastrointestinal bleeding and perforation. Epidemiology 8: Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, et al Effects of estrogen plus progestin on health-related quality of life. N. Engl. J. Med. 348: Hebert-Croteau N A meta-analysis of hormone replacement therapy and colon cancer in women. Cancer Epidemiol. Biomarkers Prev. 7: Hemminki E, McPherson K Impact of postmenopausal hormone therapy on cardiovascular events and cancer: pooled data from clinical trials. BMJ 315: Hersh AL, Stefanick ML, Stafford RS National use of postmenopausal hormone therapy. JAMA 291: Hlatky MA, Boothroyd D, Vittinghoff E, Sharp PC, Whooley M Qualityof-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial. JAMA 287: Hogervorst E, Yaffe K, Richards M, Huppert F Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Database Syst. Rev. CD Holmberg L, Anderson H HABITS (hormonal replacement therapy after breast cancer Is it safe?), a randomised comparison: trial stopped. Lancet 363: Holmberg L, Anderson H Stopping HABITS. Lancet 363: Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, et al Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA 288: a. Hulley SB, Grady D The WHI Estrogen-Alone Trial Do things look any better? JAMA 291: Hulley S, Grady D, Bush T, Furberg C, Herrington D, 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 280: Humphrey LL, Chan BK, Sox HC Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann. Intern. Med. 137: Isaacs AJ, Britton AR, McPherson K Why do women doctors in the UK take hormone replacement therapy? J. Epidemiol. Community Health 51: Kaufert P, Boggs PP, Ettinger B, Woods NF, Utian WH Women and menopause: beliefs, attitudes, and behaviors. The North American Menopause Society 1997 Menopause Survey. Menopause 5: Kronenberg F Hot flashes: epidemiology and physiology. Ann. N.Y. Acad. Sci. 592:52 86; discussion pp Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG

24 138 BARRETT-CONNOR GRADY STEFANICK Women s Healthy Lifestyle Project: a randomized clinical trial: results at 54 months. Circulation 103: Lacey JV Jr, Mink PJ, Lubin JH, Sherman ME, Troisi R, et al Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288: LeBlanc ES, Janowsky J, Chan BK, Nelson HD Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 285: Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil. Steril. 79: MacLennan A, Lester S, Moore V Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review. Climacteric 4: Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, et al Estrogen plus progestin and the risk of coronary heart disease. N. Engl. J. Med. 349: Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am. J. Epidemiol. 143: Miller J, Chan BK, Nelson HD Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann. Intern. Med. 136: Miller KJ The other side of estrogen replacement therapy: outcome study results of mood improvement in estrogen users and nonusers. Curr. Psychiatry Rep. 5: Montgomery BE, Daum GS, Dunton CJ Endometrial hyperplasia: a review. Obstet. Gynecol. Surv. 59: Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, et al Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer s Disease Cooperative Study. JAMA 283: Nieves JW, Komar L, Cosman F, Lindsay R Calcium potentiates the effect of estrogen and calcitonin on bone mass: review and analysis. Am. J. Clin. Nutr. 67: Nilas L, Christiansen C Bone mass and its relationship to age and the menopause. J. Clin. Endocrinol. Metab. 65: Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J. Intern. Med. 232: Norman RJ, Flight IH, Rees MC Oestrogen and progestogen hormone replacement therapy for peri-menopausal and post-menopausal women: weight and body fat distribution. Cochrane Database Syst. Rev. CD Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA 290: Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, et al Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women s Health Initiative Memory Study: a randomized controlled trial. JAMA 289: Raz R, Stamm WE A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N. Engl. J. Med. 329: Riggs BL, Melton LJ 3rd The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 17:505S Riman T, Dickman PW, Nilsson S, Correia N, Nordlinder H, et al

25 MENOPAUSAL HORMONE THERAPY 139 Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J. Natl. Cancer Inst. 94: Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 285: Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, et al Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women s Health Initiative randomized controlled trial. JAMA 288: Rymer J, Morris EP Extracts from clinical evidence : menopausal symptoms. BMJ 321: Scarabin PY, Oger E, Plu-Bureau G Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 362: Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, et al Estrogen replacement in perimenopause-related depression: a preliminary report. Am. J. Obstet. Gynecol. 183: Sherwin BB Can estrogen keep you smart? Evidence from clinical studies. J. Psychiatry Neurosci. 24: Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, et al Conjugated equine estrogen alone and incidence of probable dementia and mild cognitive impairment in postmenopausal women: results from the Women s Health Initiative Memory Study. JAMA 291: Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, et al Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women s Health Initiative Memory Study: a randomized controlled trial. JAMA 289: Simon JA, Hsia J, Cauley JA, Richards C, Harris F, et al Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-Progestin Replacement Study (HERS). Circulation 103: Slater CC, Zhang C, Hodis HN, Mack WJ, Boostanfar R, et al Comparison of estrogen and androgen levels after oral estrogen replacement therapy. J. Reprod. Med. 46: Smith DC, Prentice R, Thompson DJ, Herrmann WL Association of exogenous estrogen and endometrial carcinoma. N. Engl. J. Med. 293: Soares CN, Almeida OP, Joffe H, Cohen LS Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch. Gen. Psychiatry 58: Soares CN, Poitras JR, Prouty J Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause. Drugs Aging 20: Speroff L, Whitcomb RW, Kempfert NJ, Boyd RA, Paulissen JB, Rowan JP Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms. Obstet. Gynecol. 88: 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. 313: Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR The Women s Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann. Epidemiol. 13:S Torgerson DJ, Bell-Syer SE Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA 285: Utian WH, Boggs PP The North American Menopause Society

26 140 BARRETT-CONNOR GRADY STEFANICK 1998 Menopause Survey. Part I: Postmenopausal women s perceptions about menopause and midlife. Menopause 6: Utian WH, Burry KA, Archer DF, Gallagher JC, Boyett RL, et al Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. The Esclim Study Group. Am. J. Obstet. Gynecol. 181: Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil. Steril. 75: Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI A clinical trial of estrogen-replacement therapy after ischemic stroke. N. Engl. J. Med. 345: Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, et al Effect of estrogen plus progestin on stroke in postmenopausal women: the Women s Health Initiative: a randomized trial. JAMA 289: Weiss NS, Ure CL, Ballard JH, Williams AR, Daling JR Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N. Engl. J. Med. 303: Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, et al Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr. Rev. 23: Wells M, Sturdee DW, Barlow DH, Ulrich LG, O Brien K, et al Effect on endometrium of long term treatment with continuous combined oestrogenprogestogen replacement therapy: follow up study. BMJ 325: Wilson RA Feminine Forever. New York: Evans (distributed by Lippincott) 100. Ziel HK, Finkle WD Increased risk of endometrial carcinoma among users of conjugated estrogens. N. Engl. J. Med. 293: Zweifel JE, O Brien WH A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology 22:

27 Annual Review of Public Health Volume 26, 2005 CONTENTS EPIDEMIOLOGY AND BIOSTATISTICS A Life Course Approach to Chronic Disease Epidemiology, John Lynch and George Davey Smith 1 Advances in Cancer Epidemiology: Understanding Causal Mechanisms and the Evidence for Implementing Interventions, David Schottenfeld and Jennifer L. Beebe-Dimmer 37 Competing Dietary Claims for Weight Loss: Finding the Forest Through Truculent Trees, David L. Katz 61 Population Disparities in Asthma, Diane R. Gold and Rosalind Wright 89 The Rise and Fall of Menopausal Hormone Therapy, Elizabeth Barrett-Connor, Deborah Grady, and Marcia L. Stefanick 115 Magnitude of Alcohol-Related Mortality and Morbidity Among U.S. College Students Ages 18 24: Changes from 1998 to 2001, Ralph Hingson, Timothy Hereen, Michael Winter, and Henry Wechsler 259 ENVIRONMENTAL AND OCCUPATIONAL HEALTH Advances in Risk Assessment and Communication, Bernard D. Goldstein 141 EMF and Health, Maria Feychting, Anders Ahlbom, and Leeka Kheifets 165 The Public Health Impact of Prion Diseases, Ermias D. Belay and Lawrence B. Schonberger 191 Water and Bioterrorism: Preparing for the Potential Threat to U.S. Water Supplies and Public Health, Patricia L. Meinhardt 213 PUBLIC HEALTH PRACTICE Economic Causes and Consequences of Obesity, Eric A. Finkelstein, Christopher J. Ruhm, and Katherine M. Kosa 239 Magnitude of Alcohol-Related Mortality and Morbidity Among U.S. College Students Ages 18 24: Changes from 1998 to 2001, Ralph Hingson, Timothy Hereen, Michael Winter, and Henry Wechsler 259 New Microbiology Tools for Public Health and Their Implications, Betty H. Robertson and Janet K.A. Nicholson 281 vii