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International Differences in Mortality at Older Ages: Dimensions and Sources 10 Can Hormone Therapy Account for American Women’s Survival Disadvantage? Noreen Goldman Although the United States had one of the world’s highest life expectancies during the first half of the 20th century, this survival advantage gradually eroded during the ensuing decades. Of particular concern in the context of this volume is the recent stagnation in mortality improvement among middle-aged and older U.S. women relative to both U.S. men and to women in other wealthy nations (Meslé and Vallin, 2006; Vaupel, 2003). These mortality patterns suggest an appealing but as yet unexplored explanation: the use of postmenopausal hormone therapy (HT) among women in the United States. There is considerable evidence that, at least prior to 2002, estrogen-type hormones had been widely prescribed to U.S. women after the cessation of menses not only for relief of unpleasant symptoms associated with menopause but also increasingly for presumed protection against cardiovascular disease and bone loss.1 National estimates suggest a 1 Hormone therapy (known commercially as Premarin) was approved by the U.S. Food and Drug Administration for the treatment of menopausal symptoms in 1942. In 1986, it was approved for the prevention of osteoporosis. Although the Food and Drug Administration never approved Premarin or alternative forms of HT for the prevention of other chronic diseases, physicians began to widely prescribe it for these purposes because observational studies in the 1980s and 1990s suggested numerous health benefits, including cardiovascular disease and dementia prevention (Wysowski and Governale, 2005). For example, clinical guidelines in 1992 for counseling postmenopausal women indicated that those with coronary disease or at an increased risk of it would be likely to benefit from HT use; they suggested that long-term therapy would yield the most benefit for reduced risk of coronary disease and osteoporotic fractures. The guidelines also noted that “all women, regardless of race, should consider preventive hormone therapy” (American College of Physicians, 1992; Wysowski, Golden, and Burke, 1995).
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International Differences in Mortality at Older Ages: Dimensions and Sources steady increase in HT use since the early 1980s, with a prevalence of about 38 to 40 percent among women ages 50 to 74 in 1995. Data on numbers of prescriptions for all forms of HT reveal a continued increase from 1995 to 2001, with the annual number of prescriptions peaking at 92 million in 2000 (Hersh, Stefanick, and Stafford, 2004).2 The plausibility of the hypothesis that HT use underlies the U.S. survival disadvantage rests heavily on the assumption that it is a risk factor for overall mortality. If this assumption is valid, the strength of evidence implicating HT use depends on a second assertion, namely that its use has been more prevalent in the United States than in other Western populations. In this chapter, I evaluate the evidence for these assumptions. Observational studies have generally reported substantially lower rates of heart disease—on the order of 35 to 50 percent—for long-term users of postmenopausal HT compared with nonusers (Grodstein, Manson, and Stampfer, 2006; Grodstein et al., 2000; Manson and Bassuk, 2007; Prentice and Anderson, 2008). For example, in 1992, a meta-analysis based on 32 observational studies concluded that ever-users of estrogen had a relative risk of coronary heart disease of 0.65 compared with never-users, a finding generally in line with two previous meta-analysis estimates of 0.55 and 0.58 (Grady et al., 1992). However, during the past decade, randomized controlled trials (RCTs) have challenged findings from observational studies regarding the harm and benefits of long-term use of HT. Although both types of studies are in general agreement about its benefits for colorectal cancer and hip fracture and the increased risk associated with breast cancer, they have produced widely discrepant estimates for coronary heart disease or CHD (Grodstein, Clarkson, and Manson, 2003; Nelson et al., 2002). Data from the Women’s Health Initiative (WHI), a well-publicized randomized trial that administered the two dominant forms of hormone therapy to healthy U.S. women ages 50 to 79,3 suggested an increased incidence of CHD and thromboembolic events, as well as all cardiovascular disease combined, based on an average of 5.2 years of use of the estrogen-progestin regimen (Nelson et al., 2002; Writing Group for the Women’s Health Ini- 2 The two most common forms of HT in the United States are (1) a mixture of conjugated equine estrogens, typically referred to as unopposed estrogens, and (2) a combination of estrogen and progestin (a synthetic substance with effects similar to progesterone). In light of evidence suggesting an increased risk of uterine cancer associated with unopposed estrogens, women with an intact uterus have been using estrogen-progestin combinations. The majority of prescriptions in the United States have been for orally administered hormone therapy; transdermal and vaginal preparations have been used much less frequently (Hersh et al., 2004). 3 Initiated in 1992, the WHI enrolled about 27,500 postmenopausal women into two parallel clinical trials designed to evaluate the consequences of hormone therapy for disease prevention (particularly CHD and fractures). Women without a uterus were randomly assigned to receive unopposed estrogens or a placebo, and women with an intact uterus were randomly assigned to receive an estrogen-progestin combination or a placebo.
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International Differences in Mortality at Older Ages: Dimensions and Sources tiative Investigators, 2002). In the second arm of the WHI, an average of 6.8 years of use of unopposed estrogens was significantly associated with increased risk of stroke and total cardiovascular disease, but not coronary heart disease (Women’s Health Initiative Steering Committee, 2004). Both trials were terminated earlier than scheduled4 because, on balance, hormone therapy appeared to be causing more harmful outcomes than beneficial ones (Fletcher and Colditz, 2002). Widely disseminated estimates from the WHI, along with similar evidence from other RCTs,5 have led to guidelines against the routine use of hormone therapy for prevention of cardiovascular disease and to a dramatic reduction in the prevalence of postmenopausal hormone therapy beginning in 2002 or 2003 in the United States and other countries (Barbaglia et al., 2009; Coombs and Boyages, 2005; Du et al., 2007; GayetAgeron et al., 2005; Guay et al., 2007; Hersh et al., 2004; Townsend and Nanchahal, 2005; Waaseth, Bakken, and Lund, 2009). The link between hormone therapy and cardiovascular disease is a salient one for this study because cardiovascular disease is the leading cause of death among women in the United States and most Western countries. Nevertheless, the evidence from RCTs fails to support the hypothesis that HT is an important source of female mortality stagnation for two reasons. First, despite what appears to be a modest increase in overall disease events6 for users of estrogen-progestin (but not unopposed estrogen) in the WHI, the estimated risks of HT use roughly counteract the estimated benefits in terms of deaths from all causes. The WHI estimates of the hazard ratios for overall mortality, for HT use compared with a placebo, are 0.98 (95 percent CI of 0.82-1.18) for estrogen-progestin at about 6 years of use and 1.04 (95 percent CI of 0.88-1.22) for unopposed estrogen at about 7 years of use. Similarly, a meta-analysis based on about 27,000 participants in 30 RCTs conducted between 1966 and 2002 yielded an odds ratio for total mortality associated with HT of 0.98 (95 percent CI of 0.87-1.12); the average duration of these trials was 4.5 years (Salpeter et al., 2004). Thus, estimates of relative all-cause mortality risk associated with HT use are consistently close to 1. 4 The WHI estrogen-progestin trial was terminated in July 2002, and the WHI estrogen-only trial was terminated in February 2004. 5 The Heart and Estrogen/Progestin Replacement Study, which examined women with established heart disease, identified an increased risk of coronary events among HT users in the first year but not in subsequent years of the trial. The WISDOM trial in the United Kingdom demonstrated an elevation in CHD risk associated with estrogen-progestin (but not unopposed estrogen) in the first year of use; estimates for longer durations were never obtained because the trial was cancelled after the release of the WHI results. 6 The WHI computed a global health index that included the first event for each participant of CHD, stroke, pulmonary embolism, breast cancer, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.
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International Differences in Mortality at Older Ages: Dimensions and Sources Second, the argument for increased mortality risk associated with HT use is weakened by new evidence casting doubt on the earlier WHI claims. This work suggests that the widely publicized discrepancies between observational studies and randomized controlled trials may be due in large part to differences in the timing of HT initiation relative to the onset of menopause: women taking it in observational studies usually began therapy in early menopause, whereas participants in randomized trials were typically assigned to HT use at a later stage. In particular, whereas the average age of menopause in the United States is 51 years (Manson et al., 2007), the average age of the WHI sample at baseline was about 63 years, and most participants were more than a decade past the onset of menopause (Grodstein, Manson, and Stampfer, 2006).7 Similarly, the average baseline age of participants in the Heart and Estrogen/Progestin Replacement Study (HERS) was 67 (and, by study design, all began the trial with a diagnosis of CHD). In contrast, 80 percent of hormone users in the Nurses’ Health Study, the most frequently cited cohort study examining the health consequences of HT use, initiated use within a 2- to 3-year period after the start of menopause (Manson and Bassuk, 2007). A hypothesis currently under evaluation that is consistent with data from clinical trials and experimental data from nonhuman primates is that exogenous estrogen has counteracting effects on coronary function that may vary with the stage of atherosclerosis. Researchers have speculated that, at early stages, estrogen may lower coronary risk by improving lipid and endothelial function, but that the prothrombotic and proinflammatory effects of estrogen may result in clotting or rupture of plaque in the presence of advanced lesions, which are more likely to exist at later ages or durations since menopause (Manson and Bassuk, 2007). There are several recent sources of evidence to support this theory. First, a secondary analysis8 based on pooled data from the two WHI trials yielded a significant trend in relative risk for CHD, with women at higher durations since menopause onset experiencing higher relative risks than those initiating use closer to menopause (Rossouw et al., 2007). Second, a reanalysis of the Nurses’ Health Study by duration since menopause revealed a similar pattern: women initiating HT near menopause had a significantly lower risk of CHD than never-users, whereas the group of women initiating use at least 10 years after menopause was statistically indistinguishable from never-users (Grodstein, Manson, and Stampfer, 2006). Third, in a separate analysis of the Nurses’ Health Study, in which the authors used these 7 Cost and sample size considerations, as well as the fact that clinicians were frequently prescribing HT to older women for disease prevention, supported the choice of a broad age range for the WHI. 8 Data from the WHI trials were pooled because of the small number of women who were assigned to HT treatment close to the onset of menopause.
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International Differences in Mortality at Older Ages: Dimensions and Sources observational data to mimic the WHI, differences between the two sets of data were greatly attenuated after stratification by time of HT initiation (Hernan et al., 2008). Fourth, results from a recent meta-analysis indicated that, in RCTs of relatively young postmenopausal women or women within a decade of menopause onset, HT users had significantly lower CHD risk than nonusers, but this advantage was not present in studies of older women (Salpeter et al., 2006). Similarly, an earlier meta-analysis that examined mortality as an outcome found that HT was associated with lower total mortality for trials with a mean age of women under 60, but not for other trials (Salpeter et al., 2004). Fifth, data from the WHI Coronary Artery Calcium Study initiated in 2004 examined the amount of atherosclerotic calcification in the coronary arteries of women in their fifties. The results indicated that the calcified-plaque burden—a marker of total atherosclerotic plaque burden—was lower in those randomly assigned to estrogen use than in those assigned to a placebo (Manson et al., 2007), suggesting that estrogen therapy may be protective against coronary disease among women who recently began menopause. In sum, several high-quality studies undertaken since the termination of the WHI trials suggest that HT use does not result in increased CHD risk for women initiating it at younger ages or close to menopause onset9 and that use by these women may confer protection against CHD for short to moderate durations of use. Not all studies, however, support this “timing hypothesis.” A recent analysis of clinical trial and observational data from the WHI examined health outcomes for women who initiated HT use within 5 years of menopause. Although the researchers underscored the need for cautious interpretation of results because of data limitations,10 they found that, contrary to expectation, rates of coronary disease and overall mortality were not significantly different between women initiating HT near menopause onset and later initiators (Prentice et al., 2009). This ongoing controversy underscores the need for further research regarding the effects of the timing of HT onset, as well as the extent of vascular disease and duration of HT use on health outcomes. Hormone therapy may have had a negative impact on diseases other than coronary heart disease. For example, estimates from both observational studies and randomized controlled trials indicate that HT use is 9 Possible harmful effects of hormone therapy on cardiovascular health for women initiating use at older ages or durations since menopause onset may reflect the presence of significant vascular disease. 10 The broad postmenopausal age distribution of the WHI trials means that relatively few women were within 5 years of menopause at the time of randomization. Thus, this study included women who had used hormone therapy prior to enrollment in the randomized controlled trials as well as women in the WHI observational study.
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International Differences in Mortality at Older Ages: Dimensions and Sources associated with increased risk of breast cancer.11 Moreover, several studies identified reductions in breast cancer incidence subsequent to the drop in HT use that followed the publicity of the WHI findings in 2002. One U.S. study revealed a 7 percent drop in age-adjusted incidence of breast cancer in 2003 compared with 2002, but a leveling off in 2004 and thereafter (Ravdin et al., 2007). Another U.S. study indicated an 8.8 percent decrease in breast cancer incidence between 2000 and 2005 (Coombs et al., 2009). A reduction of a similar magnitude between 2001 and 2003 was reported in Australia (Canfell et al., 2008). Corresponding temporal associations between a decline in HT use and a drop in breast cancer incidence occurred in Canada, France, Germany, New Zealand, Norway, and Switzerland, but not all countries showed this relationship (Kumle, 2008; Ringa and Fournier, 2008). There is evidence that at least part of these declines can be attributed to reductions in HT use rather than to changes in mammography screening or other causes (Chlebowski et al., 2009a, 2009b; Ravdin et al., 2007). One study estimated that the 52 percent reduction in HT use that occurred between 2000 and 2005 in the United States resulted in a decrease in breast cancer incidence ranging between 2 and 8 percent, depending on assumptions regarding the relative risk of breast cancer associated with HT use (Coombs et al., 2010). Although few researchers dispute the overall link between HT use and higher rates of breast cancer, it is important to keep in mind that death rates from breast cancer are far lower than those from cardiovascular disease, and thus the impact of HT-related breast cancer on overall adult female mortality is likely to have been modest. For example, for the period between 1960 and 2000, death rates for women ages 50 and older from breast cancer were about one-twelfth as high, on average, as those from cardiovascular disease. Moreover, there are likely to have been at least partly offsetting reductions in mortality from other diseases (e.g., colon cancer) as a result of HT use. All in all, there is little evidence to date linking HT use to an increased risk of all-cause mortality in postmenopausal women.12 Nevertheless, for completeness of the argument, I consider whether the limited data available suggest a higher prevalence of HT use in the United States than in other wealthy countries. The MONICA Project of the World Health Organization (WHO) pro- 11 A recent study based on combined RCTs and observational data from the WHI found that breast cancer risks were particularly high for women who initiated HT soon after menopause and used it for many years (Prentice and Anderson, 2008). 12 A WHI postintervention study compared disease events and mortality between the estrogen-progestin group and the placebo group 3 years after the WHI trial was terminated. The HT group had higher mortality, although the difference between groups was not statistically significant. There was, however, a notable excess of deaths from lung cancer, especially nonsmall-cell lung cancer (Chlebowski et al., 2009a, 2009b; Heiss et al., 2008).
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International Differences in Mortality at Older Ages: Dimensions and Sources vides a unique source of information on the prevalence of hormone therapy across 32 nonnational populations in 20 countries; the majority of surveys were fielded between 1990 and 1995 (Lundberg et al., 2004). In most of these samples, women ages 45 to 64 were asked about HT use in the past month; no information was collected regarding the regimen or form of administration. The resulting age-standardized prevalence estimates range from a low in Moscow, Russia (0 percent) to a high in Newcastle, Australia, and Halifax, Canada (42 percent). The corresponding estimate for the United States (38 percent, derived from four communities in California) was above the average but below those for Australia and Canada and roughly equal to those for the sampled locations in France, Germany, and Iceland. Additional estimates derived from prescription or survey data from several countries suggest that the United States is not unique in having had a high prevalence of hormone therapy. For example, estimates for women ages 50-69 in France, based on eight cohort studies, indicate that over half of the women in this age group received hormone therapy in the period prior to the publication of the WHI findings (Gayet-Ageron et al., 2005). Schneider (2002) reported that, in the period 1998-2001, HT prevalence was about twice as high in France as in the United States and Germany. Data from the United Kingdom (Million Women Study Collaborators, 2002; Townsend and Nanchahal, 2005) reveal only slightly lower proportions of postmenopausal women taking hormone therapy in the period 1996-2002 in Britain (36 percent) than in the United States (38-40 percent). Estimates from a cohort study in North Norway indicate a similarly high prevalence (38 percent) among postmenopausal women in 2002 (Waaseth, Bakken, and Lund, 2009). Nevertheless, there is little doubt that HT prevalence in the United States vastly exceeded that in some countries with high life expectancy. For example, results from a community survey in Japan suggest HT prevalence in 1992 as low as 2.5 percent for women ages 45-64 (Nagata, Matsushita, and Shimizu, 1996), and data for the Netherlands indicate a prevalence of 5.6 percent in 2001 for women ages 40-74 (de Jong-van den Berg, Faber, and van den Berg, 2006). Although statistical comparisons across countries might shed some light on the strength of the association between HT prevalence and death rates for postmenopausal women, the paucity of reliable and comparable estimates of HT use preclude such analyses. Most estimates, including those from the WHO MONICA Project, are based on relatively small geographic areas and short time periods.13 Moreover, there is substantial variation across samples and countries in the quality of the HT estimates as well as 13 The available data suggest large variations in HT prevalence by time period, typically increasing prior to termination of the WHI study and declining substantially thereafter, as well as by region in a given country (see, for example, Heier’s study of HT use in Germany—Heier et al., 2009).
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International Differences in Mortality at Older Ages: Dimensions and Sources definitions of HT use. In addition, the method of administration (oral or transdermal), dose, and formulation (estrogen-progestin combination versus unopposed estrogens as well as type of progestin) of exogenous hormones vary across countries and may affect health outcomes (Fournier, Berrino, and Clavel-Chapeton, 2008; Manson et al., 2006). High-quality data on the characteristics of HT are even scarcer than estimates of its prevalence. Of particular relevance to this discussion is cross-country variation in the use of the transdermal patch. Whereas the transdermal patch is prescribed relatively infrequently in the United States, transdermal administration is the most prevalent form of hormone therapy in France and may be widely used in other countries (Fournier et al., 2008; Kim et al., 2007; Scarabin, Oger, and Plu-Bureau, 2003).14 Transdermal delivery of hormone therapy is thought to have the advantage of bypassing some of the detrimental effects of oral administration that are associated with gut and hepatic metabolism (Kopper, Gudeman, and Thompson, 2009; Stevenson, 2009). In particular, several studies suggest that oral estrogens may be more strongly associated with cardiovascular risk (e.g., elevated C-reactive protein levels or an increase in triglycerides) than nonorally administered estrogens (L’Hermite et al., 2008; Vrablik et al., 2008). In addition, there is evidence that oral but not transdermal administration is associated with an increased risk of venous thromboembolism in postmenopausal women (Scarabin, Oger, and Plu-Bureau, 2003). Thus, it is plausible that, for a given level of HT use, the negative health consequences have been greater in the United States than in some other countries, but the paucity of relevant data make it impossible to reach a firmer conclusion. In summary, there is little evidence to support the notion that higher use of HT in the United States than in other wealthy countries is likely to have resulted in mortality stagnation among middle-aged and older women. This argument is based on three sets of findings from recent studies in the United States and other wealthy countries: (1) HT use does not appear to have a notable impact on all-cause mortality; (2) HT use does not appear to be a significant risk factor for coronary heart disease and may be protective in this regard when initiated near the onset of menopause; and (3) although high, HT prevalence in the United States prior to the recent decline is similar to 14 Data from Berlin, Germany, and Quebec, Canada, suggest that, as in the United States, transdermal application of HT has been much less common that oral administration in these locations (Du et al., 2009; Guay et al., 2007). There are differences in formulations across countries as well. For example, in the period just prior to the termination of the WHI, unopposed estrogens were prescribed more frequently than estrogen-progestin combinations for postmenopausal women in the United States and Australia (Hersh et al., 2004; Main and Robinson, 2008). However, the Million Women Study found that HT users in the period 1996-2000 in the United Kingdom were more likely to use estrogen-progestin combinations than estrogen alone (Million Women Study Collaborators, 2002).
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International Differences in Mortality at Older Ages: Dimensions and Sources rates of use in several countries that have experienced steady improvements in female life expectancy. Although the major RCTs related to hormone therapy have been terminated, research on the health consequences of HT use has not abated. Analyses based on continued follow-up of participants in the randomized trials, smaller scale trials examining the biological pathways linking HT to cardiovascular disease, and observational studies are likely to provide updated and longer term estimates of the consequences of HT for health and survival in the United States and elsewhere. REFERENCES American College of Physicians. (1992). Guidelines for counseling postmenopausal women about preventive hormone therapy. Annals of Internal Medicine, 117, 1038-1041. Barbaglia, G., Macia, F., Comas, M., Sala, M., del Mar Vernet, M., Casamitjana, M., and Castells, X. (2009). Trends in hormone therapy use before and after publication of the Women’s Health Initiative trial: 10 years of follow-up. Menopause: Journal of the North American Menopause Society, 16(5), 1061-1064. Canfell, K., Banks, E., Moa, A.M., and Beral, V. (2008). Decrease in breast cancer incidence following a rapid fall in use of hormone replacement therapy in Australia. Medical Journal of Australia, 188(11), 641-644. Chlebowski, R.T., Kuller, L.H., Prentice, R.L., Stefanick, M.L., Manson, J.E., Gass, M., Aragaki, A.K., Ockene, J.K., Lane, D.S., Sarto, G.E., Rajkovic, A., Schenken, R., Hendrix, S.L., Ravdin, P.M., Rohan, T.E., Yasmeen, S., Anderson, G., and the WHI investigators. (2009a). Breast cancer after use of estrogen plus progestin in postmenopausal women. New England Journal of Medicine, 360(6), 573-587. Chlebowski, R.T., Schwartz, A.G., Wakelee, H., Anderson, G.L., Stefanick, M.L., Manson, J.E., Rodabough, R.J., Chien, J.W., Wactawski-Wende, J., Gass, M., Kotchen, J.M., Johnson, K.C., O’Sullivan, M.J., Ockene, J.K., Chen, C., and Hubbell, F.A. (2009b). Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): A post-hoc analysis of a randomised controlled trial. Lancet, 374(9697), 1243-1251. Coombs, N.J., and Boyages, J. (2005). Changes in HT prescriptions in Australia since 1992. Australian Family Physician, 34(8), 697-698. Coombs, N.J., Cronin, K.A., Taylor, R.J., Freedman, A.N., and Boyages, J. (2010). The impact of changes in hormone therapy on breast cancer incidence in the U.S. population. Cancer Causes and Control, 21(1), 83-90. de Jong-van den Berg, L.T.W., Faber, A., and van den Berg, P.B. (2006). HRT use in 2001 and 2004 in the Netherlands—A world of difference. Maturitas, 54(2), 193-197. Du, Y., Doren, M., Melchert, H., Scheidt-Nave, C., and Knopf, H. (2007). Differences in menopausal hormone therapy use among women in Germany between 1998 and 2003. BMC Women’s Health, 7(1), 19. Du, Y., Schneidt-Nave, C., Schaffrath Rosario, A., Ellert, U., Doren, M., and Knopf, H. (2009). Changes of menopausal hormone therapy use pattern since 2000: Results of the Berlin Spandau Longitudinal Health Study. Climacteric, 12(4), 329-340. Fletcher, S.W., and Colditz, G.A. (2002). Failure of estrogen plus progestin therapy for prevention. Journal of the American Medical Association, 288, 366-368. Fournier, A., Berrino, F., and Clavel-Chapeton, F. (2008). Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study. Breast Cancer Research and Treatment, 107(1), 103-111.
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