CLIMACTERIC 2014;17(Suppl 2):12–17
What the future holds for women after menopause: where we have been, where we are, and where we want to go R. A. Lobo Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA
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Key words: MENOPAUSE, FUTURE, MHT, PREVENTION, CORONARY HEART DISEASE, MORTALITY, PERSONALIZED MEDICINE
ABSTRACT With an increasing world population of postmenopausal women, providers of health care need to focus on improving the quality of life as well as the longevity of women. This review emphasizes the importance of health care for postmenopausal women, particularly the role of menopausal hormonal therapy (MHT), from the perspective of where we have been, where we are now, and where we can expect to be in the future. Use of MHT increased dramatically in the 1980s and then fell very abruptly in the early 2000s with the publications of various randomized hormonal trials, including the Women’s Health Initiative (WHI). The recent publications from the WHI with 13 years of follow-up are different from the initial reports and do not show an increase in cardiovascular risk in any age group (with the exception of venous thrombosis). Breast cancer risk increased marginally with estrogen/progestogen therapy, related to duration of use, but with estrogen-alone therapy, breast cancer risk decreased significantly, as did mortality. For younger women receiving estrogen alone, there is great consistency between all randomized trials, including the WHI and observational data showing a coronary benefit and a decrease in all-cause mortality. Recent data also confirm the ‘timing hypothesis’, suggesting that younger women benefit from MHT, while older women do not exhibit this effect. In the future, we will have many more genetic and molecular tools to guide therapy and risk assessment, as we move into an era of personalized medicine. An important opportunity presents at the onset of menopause to prevent diseases which usually occur some 10 years later. Part of this preventative strategy may involve MHT.
INTRODUCTION
WHERE WE HAVE BEEN
Life expectancy at present is over 80 years for women in most of the developed world, resulting in women spending 30 or more years of life after menopause. A large segment of the world’s population is postmenopausal, with an estimated 60 million women by 2020 in the US alone1. Thus, assuring that this long period of time after menopause for millions of women worldwide is healthy and of good quality should be the goal of all providers of health care for women. The general focus of this review is the health care of women after menopause; more specifically, however, it frames our current understanding of the use of menopausal hormonal therapy (MHT). It begins with a brief history of the milestones in MHT, and then assesses its current status and finally takes a look into the future.
Beginning in the late 1930s and early 1940s, synthetic estrogen preparations were available for treatment. The concept of ‘feminine forever’ was advanced by Robert Wilson in 1966, suggesting that all women should receive hormones after menopause. Although this was widely controversial, and Wilson was eventually ostracized by medical societies, many women received hormone preparations. Estrogens were prescribed at a steady rate up to the 1980s when prescriptions for Premarin, the major product, increased significantly after the Food and Drug Administration (FDA) approved Premarin for the prevention of osteoporotic fractures in 1988; Premarin had been approved for use since May 1942. This increase occurred despite reports in 1975 that found that
Correspondence: Professor R. A. Lobo, Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA; E-mail: ral35@ columbia.edu REVIEW © 2014 International Menopause Society DOI: 10.3109/13697137.2014.944497
Received 07-07-2014 Accepted 10-07-2014
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What the future holds for women after menopause estrogen-alone therapy (without progestogen) in women with a uterus led to an increased rate of endometrial cancer; these reports only caused a transitory drop in prescriptions. Subsequently, with the results of many observational studies showing benefit for osteoporosis, coronary disease, all-cause mortality and prevention of Alzheimer’s disease, and an inconsistent effect on breast cancer risk, sales increased manifold2. The addition of progestogen to estrogen therapy (now referred to as MHT) began to be a prominent feature of therapy by the late 1970s. The most compelling evidence for the use of MHT arose from data on the effects of estrogen on coronary heart disease (CHD) that were subjected to meta-analysis and showed a 50% reduction in CHD with the use of estrogen3. Since coronary disease is the leading cause of death in women and accelerates after menopause, with a high case fatality rate, the reduction in all-cause mortality of 20–40% which was reported in several studies was explained largely by the reduction in CHD4,5. Counterbalancing this, the risk of breast cancer was still unclear and was considered to be at most only marginally increased6. Furthermore, the case fatality rate of these breast cancers was lower, with reports of no increase, or a decrease in mortality with breast cancer among users of estrogen, which was confirmed recently7. Similarly, the data on stroke risk were inconsistent with several observational studies suggesting a decreased risk among older women8. Multiple mechanisms were believed to be operative for the protective effects of estrogen on the cardiovascular system9,10. At the same time, data emerged from smaller clinical trials that the addition of progestogen may attenuate this benefit. For example, attenuating the increase in high density lipoprotein (HDL) cholesterol with oral estrogen with progestogen addition was suggested to influence the number of lives saved from the cardioprotective effects of estrogen use. In 1988, a progestogen consensus meeting was convened to discuss the important issue of progestogen addition and the concern of this potential attenuating effect11. While there were no definitive data on which to draw conclusions, the attenuating effect of progestogens was widely acknowledged. It is interesting that this is much the same situation as we are in today where we have suggestive evidence of a negative effect of progestogens, but no proof. Indeed, the different effects between estrogen alone and estrogen/progestogen in the Women’s Health Initiative (WHI) clinical trials, described below, were not head-to-head comparisons and were carried out in different populations of women. In order to obtain an FDA-approved indication for prevention of CHD, randomized, controlled trial data were required. Several secondary prevention trials were initiated in women with established CHD. These did not find any benefit12,13 and, in addition, in some studies ‘early harm’ was witnessed, that is more coronary events observed soon after initiation (within the first 1–2 years)12 .This was followed by initial14 and subsequent data from the hormone trials of the WHI, which have been extensively reviewed15 and will not be repeated here. The initial results published in 2002 and soon thereafter were decidedly negative and raised concerns of much greater risks (largely
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Lobo cardiovascular and breast) than benefit for all women. This message was aggressively pursued by the WHI investigators and the National Institutes of Health. The communications to the media were not explained nor put into perspective, and it was stated that the increased risk pertained to all age groups16. Most women on hormone therapy stopped abruptly before clinicians had an opportunity to review the data.
WHERE WE ARE NOW Decrease in use of MHT occurred dramatically, beginning around 200217,18. Use was noted to be only 4.7% in women over 40 years old in the US in 2010, while it was 22.4% around 200018. This trend was similar around the world19. In subsequent publications from the WHI, the point estimates for risk changed, as reviewed by us previously20. By 2006, the breast cancer and cardiovascular risks initially reported for conjugated equine estrogens (CEE)/medroxyprogesterone acetate (MPA) therapy were no longer statistically significant. For breast cancer, in contrast to the original publication21 after adjustments for variables, the hazard ratio (HR) was 1.2 (95% confidence interval (CI) 0.94–1.53) and was not significant22. Moreover, the risks with CEE/MPA were confined to women who had received MHT previously, suggesting a longer cumulative exposure to hormones22. The increase in breast cancer risk for women never receiving MHT in the past did not increase until after 5 years, and possibly only after 7 years of use. At the same time, it was reported that, with CEE-alone therapy, there was a significant decrease in breast cancer23. In 2006, the WHI reported for the first time differences in risks of CHD by age stratification and time from menopause. With CEE alone, there was clearly a trend to benefit in younger women, aged 50–59 years or ⬍ 10 years from menopause. Using a composite coronary score, women aged 50–59 years had a statistical benefit with CEE alone24. In 2007, the WHI published an age/time from menopause stratification for cardiovascular risks, which showed benefit in the younger women and, when combining CEE and CEE/MPA groups, there was a statistically significant reduction in allcause mortality (HR 0.70; 95% CI 0.51–0.96)25. This was completely in line with older observational studies which were based on women who were treated for symptoms, close to the time of menopause and were younger. As women become older, coronary atherosclerosis progresses and estrogen action is no longer possible. Further, in this population, there is the increased probability that plaque instability induced by oral estrogen will lead to early harm, as was found among some older women in the WHI and in the secondary prevention trials. Subsequent meta-analyses on CHD outcomes and mortality in women ⬍ 60 years from various randomized trials, including data from the WHI, also showed a significant benefit in younger women26,27. An approximately 30% reduction in coronary events and in all-cause mortality was found26,27. Follow-up studies from the WHI (including 10- and 13-year data) were published in 2011 and 201328,29. The 10-year
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What the future holds for women after menopause
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Table 1 Cumulative 13-year data from the 50–59-year-old group in the Women’s Health Initiative trial receiving conjugated equine estrogens29
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Coronary heart disease Myocardial infarction Breast cancer All cancers Global index Total mortality
Hazard ratio
95% confidence interval
Absolute change per 10 000 woman-years
0.65 0.60 0.76 0.80 0.82 0.78
0.44–0.96 0.39–0.91 0.52–1.11 0.64–0.99 0.82–0.98 0.59–1.03
⫺11 ⫺11 ⫺7 ⫺18 ⫺26 ⫺12
follow-up data for CEE alone showed statistically significant reduced hazard ratios in the 50–59-year-old group for CHD and myocardial infarction and a 30% reduction in total mortality28. In the 13-year data set, combining the intervention and follow-up phases with CEE/MPA, CHD was not increased in the entire group (HR 1.09; 95% CI 0.96–1.24), or in any individual age group, as was published in the earlier reports20. In the 50–59-year-old group receiving CEE/MPA, there was no increase in CHD or stroke, but there was an increase in breast cancer (HR 1.34; 95% CI 1.03–1.75)29, probably reflecting a longer cumulative exposure to hormones in the women who got breast cancer, as noted above. Here, mortality also trended downwards in the younger women but was not significant (HR 0.88; 95% CI 0.70–1.11). While breast cancer was increased (HR 1.28; 95% CI 1.11–1.48) for the entire group with CEE/MPA, it was significantly decreased with CEE alone (HR 0.79; 95% CI 0.65–0.97)29 which is consistent with the original report23 and the 10-year data28. For the 50–59-year-old women, the 13-year cumulative data for CEE alone are depicted in Table 1. CHD, myocardial infarction, all cancers and the global index were all significantly reduced; mortality was reduced (HR 0.78) but did not reach statistical significance. The mortality data generated from observational and randomized, controlled trials on mortality show extreme consistency – an approximate 30% reduction in mortality in young women treated with MHT (Table 2).
The position statement of the International Menopause Society in 2013 was informed by these findings30, but it was published before the 13-year cumulative data were available. In essence, the statement suggests that, in women younger than 60 years and within 10 years of menopause, estrogenalone therapy may afford cardioprotective effects in line with older observational data. The data, however, are not as clear with the addition of progestogen, perhaps suggesting an attenuating effect, as was envisioned in 1988 at the time of the progestogen consensus meeting discussed above11. Further, in older women, standard-dose MHT may precipitate early harm and does not have the protective effect witnessed in younger women. Since most women stopped taking hormones around 2002, we now have follow-up data in many women who stopped treatment. These data show an increased rate of osteoporotic fractures31,32. In addition, in a mathematical model using theoretical calculations in hysterectomized women, it was suggested that withholding estrogen from women aged 50–59 years over a 10-year period in the US may have led to an excess mortality of between 18 000 and 91 000 women33. Because of the finding of benefit rather than harm in younger women in the WHI, which was consistent with the findings of older observational data, the focus of the most recent prospective MHT trials was to highlight the coronary effects of estrogen in younger women close to menopause. The three relevant trials are the Kronos Early Estrogen Prevention Study (KEEPS), the Early versus Late Intervention Trial with Estradiol (ELITE), and the Danish Osteoporosis Prevention Study (DOPS). KEEPS only studied 727 younger women within 3 years of menopause and compared CEE 0.45 mg with transdermal estradiol 0.05 mg and placebo for 4 years. Oral micronized progesterone 200 mg was used for 12 days each month. This relatively small study in younger women could not assess hard endpoints such as myocardial infarction but used the endpoints of carotid intima-media thickness (IMT) and coronary calcium. KEEPS failed to show any differences between estrogen and placebo34. A consideration for this null effect was that the women in this trial were selected for good cardiovascular health and were too healthy to show any differences over this relatively short interval of time. Indeed, while women were excluded from the trial if they had significant
Table 2 Consistency of data on the decreased mortality in younger women receiving estrogen in observational studies and randomized trials
Meta-analysis of observational studies27 Meta-analysis of randomized trials27 Bayesian meta-analysis27 WHI combined trials in 50–59-year-old women25 WHI 10-year data with CEE in 50–59-year-old women28 WHI 13-year data with CEE in 50–59-year-old women29 WHI 13-year-data with CEE/MPA in 50–59-year-old women29
Hazard ratio
95% confidence interval
0.78 0.73 0.72 0.70 0.73 0.78 0.88
0.69–0.90 0.52–0.96 0.62–0.82 0.51–0.96 0.53–1.0 0.59–1.03 0.70–1.1
WHI, Women’s Health Initiative; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate
14
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What the future holds for women after menopause coronary calcium at baseline, in women who had measureable coronary calcium at study onset, the women in the estrogen arms had less accumulation than those in the placebo arm, although this was not statistically significant. ELITE was more of a true test of the ‘timing hypothesis’, studying 643 women who were either within 6 years of menopause or 10 or more years from the time of menopause. Oral estradiol 1 mg was prescribed versus placebo and vaginal estrogen was used for 10 days monthly. The main endpoint, carotid IMT, was decreased after 6 years with oral estrogen in women within 6 years of menopause and was increased in the older women35. These preliminary data confirm the timing hypothesis showing that younger women benefit from estrogen by inhibiting atherosclerosis while older women fail to respond. In 2012, DOPS reported on 1006 women who, at the onset of menopause, were prospectively treated with estrogen (estradiol) alone or estrogen/progestogen (norethindrone acetate) versus no treatment for 10 years, with 16 years of follow-up36. A composite endpoint of mortality, hospitalization for congestive failure or myocardial infarction was significantly reduced in women on MHT and appeared to be more reduced, the younger the women were. There were also no adverse effects reported in this smaller group of women in terms of stroke, deep vein thrombosis or breast cancer36. In summary, the data we have at hand today (randomized trials including the WHI, meta-analyses, older observational studies, ELITE and DOPS) are consistent in showing a protective effect on atherosclerosis progression, coronary events and mortality in healthy young women who initiate therapy at the onset of menopause, but not in older women. The data are predominantly with the use of oral estrogen (CEE or estradiol) and the potential attenuating effects of MPA or any particular progestogen, while likely, remain uncertain at present.
WHERE WE WANT TO GO It first needs to be appreciated that there are risks in anything one does. As we suggest interventions to improve longevity and the quality of the lives of women, no action is totally risk-free. The absolute risks in a 50–59-year-old woman receiving CEE or CEE/MPA for 5–6 years according to data from the WHI is no more than five to six events/10 000 women29; this only pertains to data for breast cancer and thrombosis. The majority of effects are actually beneficial. While there remains some controversy over the ischemic stroke data in younger women in the WHI, the most recent cumulative data show no significant effect. On the other side of the coin, the therapeutic benefits in terms of reducing vasomotor symptoms and vaginal atrophy are in the range of 8000–9000/10 000 women37. Given that most effects in the 50–59-year-old group are beneficial, the magnitude of the hazard, for example the risk for breast cancer with CEE/MPA with longer-term therapy (not CEE alone), should be compared with some other naturally occurring annual risks. The risk of death in a motor vehicle accident is 1/6500; the risk
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Lobo of death from walking across the street is 1/48 500, and that from drowning or a fire is 1/88 000. The risk of having a car stolen is 1/100 and of having a house fire is 1/20038. There are even risks of myocardial infarction and mortality with taking supplemental calcium39. Indeed, for breast cancer, the relative risks are far greater if a woman has certain endogenous risks such as increased breast density or obesity than with the use of MHT40. As we move into the future, we are entering an era of personalized medicine. With sophisticated genetic and molecular tools, we are beginning to be able to catalogue the risks for breast cancer and CVD, for example, and know better how to intervene. At present, we already have a few tools. We know about probing for BRCA-1/2 genes to prevent breast and ovarian cancer41. The risk of breast cancer with MHT (both increased and decreased) has been associated with polymorphisms of the steroid receptor family42. Currently, however, genome-wide association studies have suggested that this interaction of various single nucleotide polymorphisms is too imprecise for wide application43. Estrogen receptor (ER) polymorphisms have also been identified regarding mortality outcomes with MHT44. Several polymorphisms affecting hepatic estrogen metabolism have been associated with thrombosis risk45,46. There may also be some association between ERα variants and severe depressive symptoms after menopause47. Perhaps the most knowledge we have in this area is in pharmacogenomics. Based again on genetic polymorphisms related to drug metabolism, we know what drug responses will be (increased or decreased) for a variety of drugs, such as warfarin, statins, and anti-platelet therapy48. Even the estrogenic response of increasing HDL cholesterol concentrations with oral estrogen is influenced by the particular genotype of ERα a woman has49. It can easily be envisioned that, in the near future, a simple blood test, coupled with family history, will provide a profile of future risks and responses to various medications including hormones. Thus, as we go into the future, assuring the health, quality of life and longevity of postmenopausal women will be based on preventative therapy. Menopause heralds an important opportunity to make appropriate adjustments to prevent diseases which begin to emerge 10 years later50. The path moving forward is then to initiate a comprehensive assessment including genetic and molecular tools, as they emerge, to define risks of disease and to intervene as needed. A prescription for healthy lifestyle and mental activities to prevent dementia will include specific exercises and diets depending on prediction models. If medical therapy is needed, pharmacogenomics will guide appropriate prescriptions and dose. As part of the choice for prevention therapies, MHT at the onset of menopause may be considered as part of this armamentarium50. In symptomatic women, the choice of MHT is clear and straightforward, as it is in those younger women who have a greater risk for osteoporotic fracture. In other women, assessments of risks and family history and other diagnostic tools may allow the clinician to consider MHT, specifically the use of estrogen for prevention. In younger women at the onset of menopause, there are
15
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What the future holds for women after menopause compelling observational and randomized, controlled trial data that estrogen decreases CVD and mortality. While some of the randomized, controlled trial data are subanalyses, as in the WHI, the consistency of the entire body of literature available to us, particularly with long-term data – women followed for 10 years or more, makes the argument more acceptable. It also needs to be appreciated that, apart from lifestyle changes, there is no other validated primary prevention therapy to prevent CVD in women50. Accepted therapies in men, such as statin and aspirin use, do not have the same effects in women50. Nevertheless, while the choice of the type of MHT is likely to be critical, there is no single product or regimen that can be endorsed. At present, we are not clear about types of estrogen, routes of administration or the best progestogen for women with a uterus. It is clear, however, that there are some additional risks of added progestogen in terms of breast cancer and thrombosis risks30. While there are some data suggesting that natural progesterone may be more beneficial, the data are still preliminary. Similarly, whether
Lobo the addition of a selective estrogen receptor modulator such as bazedoxifene may also be of benefit as an alternative to any progestogen is a potential51, but requires more study. Finally, it is not clear for how long therapy should be continued, particularly if symptoms are no longer the concern. There are some data that even short-term treatment at the onset of menopause may be of long-term benefit in preventing osteoporosis and cognitive decline52,53. More work is clearly needed in this area. In the final analysis, individualization is key; continuous ongoing assessment and the use of new diagnostic tools for efficacy and risks, and therapeutic adjustments as necessary, will insure the best welfare of postmenopausal women. Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
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Lobo 40. Santen RJ, Kronenberg HM, Melmed S, et al. Endocrine responsive cancer. In Williams Textbook of Endocrinology, 11th edn. Philadelphia: Saunders Elsevier, 2008:1764 41. Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med 2007; 357:154–62 42. Marie-Genica Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk. Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy. Int J Cancer 2010;126:2935–46 43. Hein R, Flesch-Janys D, Dahmen N, et al. A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication. Breast Cancer Res 2013;138:529–42 44. Ryan J, Canonico M, Carcaillon L, et al. Hormone treatment, estrogen receptor polymorphisms and mortality: a prospective cohort study. PLoS One 2012;7:e34112 45. Bouligand J, Cabaret O, Canonico M, et al. Effect of NFE2L2 genetic polymorphism on the association between oral estrogen therapy and the risk of venous thromboembolism in postmenopausal women. Clin Pharmacol Ther 2011;89:60–4 46. Canonico M, Bouaziz E, Carcaillon L, et al. Synergism between oral estrogen therapy and cytochrome P450 3A5*1 allele on the risk of venous thromboembolism among postmenopausal women. J Clin Endocrinol Metab 2008;93:3082–7 47. Ryan J, Ancelin ML. Polymorphisms of estrogen receptors and risk of depression: therapeutic implications. Drugs 2012; 72:1725–38 48. Yip VL, Pirmohamed M. Expanding role of pharmacogenomics in the management of cardiovascular disorders. Am J Cardiovasc Drugs 2013;13:151–62 49. Herrington DM, Howard TD, Hawkins GA, et al. Estrogenreceptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002;346:967–74 50. Lobo RA, Davis SR, De Villiers TJ, et al. Prevention of diseases after menopause. Climacteric 2014 June 27. Epub ahead of print 51. Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. Steroids 2014 June 14. Epub ahead of print 52. Bagger YZ, Tanko LB, Alexandersen P, et al. Two to three years of hormone replacement treatment in healthy women have longterm preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 2004;34:728–35 53. Bagger YZ, Tanko LB, Alexandersen P, et al. Early postmenopausal hormone therapy may prevent cognitive impairment later in life. Menopause 2005;12:12–17
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What the future holds for women after menopause: where we have been, where we are, and where we want to go R. A. Lobo Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA
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Key words: MENOPAUSE, FUTURE, MHT, PREVENTION, CORONARY HEART DISEASE, MORTALITY, PERSONALIZED MEDICINE
ABSTRACT With an increasing world population of postmenopausal women, providers of health care need to focus on improving the quality of life as well as the longevity of women. This review emphasizes the importance of health care for postmenopausal women, particularly the role of menopausal hormonal therapy (MHT), from the perspective of where we have been, where we are now, and where we can expect to be in the future. Use of MHT increased dramatically in the 1980s and then fell very abruptly in the early 2000s with the publications of various randomized hormonal trials, including the Women’s Health Initiative (WHI). The recent publications from the WHI with 13 years of follow-up are different from the initial reports and do not show an increase in cardiovascular risk in any age group (with the exception of venous thrombosis). Breast cancer risk increased marginally with estrogen/progestogen therapy, related to duration of use, but with estrogen-alone therapy, breast cancer risk decreased significantly, as did mortality. For younger women receiving estrogen alone, there is great consistency between all randomized trials, including the WHI and observational data showing a coronary benefit and a decrease in all-cause mortality. Recent data also confirm the ‘timing hypothesis’, suggesting that younger women benefit from MHT, while older women do not exhibit this effect. In the future, we will have many more genetic and molecular tools to guide therapy and risk assessment, as we move into an era of personalized medicine. An important opportunity presents at the onset of menopause to prevent diseases which usually occur some 10 years later. Part of this preventative strategy may involve MHT.
INTRODUCTION
WHERE WE HAVE BEEN
Life expectancy at present is over 80 years for women in most of the developed world, resulting in women spending 30 or more years of life after menopause. A large segment of the world’s population is postmenopausal, with an estimated 60 million women by 2020 in the US alone1. Thus, assuring that this long period of time after menopause for millions of women worldwide is healthy and of good quality should be the goal of all providers of health care for women. The general focus of this review is the health care of women after menopause; more specifically, however, it frames our current understanding of the use of menopausal hormonal therapy (MHT). It begins with a brief history of the milestones in MHT, and then assesses its current status and finally takes a look into the future.
Beginning in the late 1930s and early 1940s, synthetic estrogen preparations were available for treatment. The concept of ‘feminine forever’ was advanced by Robert Wilson in 1966, suggesting that all women should receive hormones after menopause. Although this was widely controversial, and Wilson was eventually ostracized by medical societies, many women received hormone preparations. Estrogens were prescribed at a steady rate up to the 1980s when prescriptions for Premarin, the major product, increased significantly after the Food and Drug Administration (FDA) approved Premarin for the prevention of osteoporotic fractures in 1988; Premarin had been approved for use since May 1942. This increase occurred despite reports in 1975 that found that
Correspondence: Professor R. A. Lobo, Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA; E-mail: ral35@ columbia.edu REVIEW © 2014 International Menopause Society DOI: 10.3109/13697137.2014.944497
Received 07-07-2014 Accepted 10-07-2014
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What the future holds for women after menopause estrogen-alone therapy (without progestogen) in women with a uterus led to an increased rate of endometrial cancer; these reports only caused a transitory drop in prescriptions. Subsequently, with the results of many observational studies showing benefit for osteoporosis, coronary disease, all-cause mortality and prevention of Alzheimer’s disease, and an inconsistent effect on breast cancer risk, sales increased manifold2. The addition of progestogen to estrogen therapy (now referred to as MHT) began to be a prominent feature of therapy by the late 1970s. The most compelling evidence for the use of MHT arose from data on the effects of estrogen on coronary heart disease (CHD) that were subjected to meta-analysis and showed a 50% reduction in CHD with the use of estrogen3. Since coronary disease is the leading cause of death in women and accelerates after menopause, with a high case fatality rate, the reduction in all-cause mortality of 20–40% which was reported in several studies was explained largely by the reduction in CHD4,5. Counterbalancing this, the risk of breast cancer was still unclear and was considered to be at most only marginally increased6. Furthermore, the case fatality rate of these breast cancers was lower, with reports of no increase, or a decrease in mortality with breast cancer among users of estrogen, which was confirmed recently7. Similarly, the data on stroke risk were inconsistent with several observational studies suggesting a decreased risk among older women8. Multiple mechanisms were believed to be operative for the protective effects of estrogen on the cardiovascular system9,10. At the same time, data emerged from smaller clinical trials that the addition of progestogen may attenuate this benefit. For example, attenuating the increase in high density lipoprotein (HDL) cholesterol with oral estrogen with progestogen addition was suggested to influence the number of lives saved from the cardioprotective effects of estrogen use. In 1988, a progestogen consensus meeting was convened to discuss the important issue of progestogen addition and the concern of this potential attenuating effect11. While there were no definitive data on which to draw conclusions, the attenuating effect of progestogens was widely acknowledged. It is interesting that this is much the same situation as we are in today where we have suggestive evidence of a negative effect of progestogens, but no proof. Indeed, the different effects between estrogen alone and estrogen/progestogen in the Women’s Health Initiative (WHI) clinical trials, described below, were not head-to-head comparisons and were carried out in different populations of women. In order to obtain an FDA-approved indication for prevention of CHD, randomized, controlled trial data were required. Several secondary prevention trials were initiated in women with established CHD. These did not find any benefit12,13 and, in addition, in some studies ‘early harm’ was witnessed, that is more coronary events observed soon after initiation (within the first 1–2 years)12 .This was followed by initial14 and subsequent data from the hormone trials of the WHI, which have been extensively reviewed15 and will not be repeated here. The initial results published in 2002 and soon thereafter were decidedly negative and raised concerns of much greater risks (largely
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Lobo cardiovascular and breast) than benefit for all women. This message was aggressively pursued by the WHI investigators and the National Institutes of Health. The communications to the media were not explained nor put into perspective, and it was stated that the increased risk pertained to all age groups16. Most women on hormone therapy stopped abruptly before clinicians had an opportunity to review the data.
WHERE WE ARE NOW Decrease in use of MHT occurred dramatically, beginning around 200217,18. Use was noted to be only 4.7% in women over 40 years old in the US in 2010, while it was 22.4% around 200018. This trend was similar around the world19. In subsequent publications from the WHI, the point estimates for risk changed, as reviewed by us previously20. By 2006, the breast cancer and cardiovascular risks initially reported for conjugated equine estrogens (CEE)/medroxyprogesterone acetate (MPA) therapy were no longer statistically significant. For breast cancer, in contrast to the original publication21 after adjustments for variables, the hazard ratio (HR) was 1.2 (95% confidence interval (CI) 0.94–1.53) and was not significant22. Moreover, the risks with CEE/MPA were confined to women who had received MHT previously, suggesting a longer cumulative exposure to hormones22. The increase in breast cancer risk for women never receiving MHT in the past did not increase until after 5 years, and possibly only after 7 years of use. At the same time, it was reported that, with CEE-alone therapy, there was a significant decrease in breast cancer23. In 2006, the WHI reported for the first time differences in risks of CHD by age stratification and time from menopause. With CEE alone, there was clearly a trend to benefit in younger women, aged 50–59 years or ⬍ 10 years from menopause. Using a composite coronary score, women aged 50–59 years had a statistical benefit with CEE alone24. In 2007, the WHI published an age/time from menopause stratification for cardiovascular risks, which showed benefit in the younger women and, when combining CEE and CEE/MPA groups, there was a statistically significant reduction in allcause mortality (HR 0.70; 95% CI 0.51–0.96)25. This was completely in line with older observational studies which were based on women who were treated for symptoms, close to the time of menopause and were younger. As women become older, coronary atherosclerosis progresses and estrogen action is no longer possible. Further, in this population, there is the increased probability that plaque instability induced by oral estrogen will lead to early harm, as was found among some older women in the WHI and in the secondary prevention trials. Subsequent meta-analyses on CHD outcomes and mortality in women ⬍ 60 years from various randomized trials, including data from the WHI, also showed a significant benefit in younger women26,27. An approximately 30% reduction in coronary events and in all-cause mortality was found26,27. Follow-up studies from the WHI (including 10- and 13-year data) were published in 2011 and 201328,29. The 10-year
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What the future holds for women after menopause
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Table 1 Cumulative 13-year data from the 50–59-year-old group in the Women’s Health Initiative trial receiving conjugated equine estrogens29
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Coronary heart disease Myocardial infarction Breast cancer All cancers Global index Total mortality
Hazard ratio
95% confidence interval
Absolute change per 10 000 woman-years
0.65 0.60 0.76 0.80 0.82 0.78
0.44–0.96 0.39–0.91 0.52–1.11 0.64–0.99 0.82–0.98 0.59–1.03
⫺11 ⫺11 ⫺7 ⫺18 ⫺26 ⫺12
follow-up data for CEE alone showed statistically significant reduced hazard ratios in the 50–59-year-old group for CHD and myocardial infarction and a 30% reduction in total mortality28. In the 13-year data set, combining the intervention and follow-up phases with CEE/MPA, CHD was not increased in the entire group (HR 1.09; 95% CI 0.96–1.24), or in any individual age group, as was published in the earlier reports20. In the 50–59-year-old group receiving CEE/MPA, there was no increase in CHD or stroke, but there was an increase in breast cancer (HR 1.34; 95% CI 1.03–1.75)29, probably reflecting a longer cumulative exposure to hormones in the women who got breast cancer, as noted above. Here, mortality also trended downwards in the younger women but was not significant (HR 0.88; 95% CI 0.70–1.11). While breast cancer was increased (HR 1.28; 95% CI 1.11–1.48) for the entire group with CEE/MPA, it was significantly decreased with CEE alone (HR 0.79; 95% CI 0.65–0.97)29 which is consistent with the original report23 and the 10-year data28. For the 50–59-year-old women, the 13-year cumulative data for CEE alone are depicted in Table 1. CHD, myocardial infarction, all cancers and the global index were all significantly reduced; mortality was reduced (HR 0.78) but did not reach statistical significance. The mortality data generated from observational and randomized, controlled trials on mortality show extreme consistency – an approximate 30% reduction in mortality in young women treated with MHT (Table 2).
The position statement of the International Menopause Society in 2013 was informed by these findings30, but it was published before the 13-year cumulative data were available. In essence, the statement suggests that, in women younger than 60 years and within 10 years of menopause, estrogenalone therapy may afford cardioprotective effects in line with older observational data. The data, however, are not as clear with the addition of progestogen, perhaps suggesting an attenuating effect, as was envisioned in 1988 at the time of the progestogen consensus meeting discussed above11. Further, in older women, standard-dose MHT may precipitate early harm and does not have the protective effect witnessed in younger women. Since most women stopped taking hormones around 2002, we now have follow-up data in many women who stopped treatment. These data show an increased rate of osteoporotic fractures31,32. In addition, in a mathematical model using theoretical calculations in hysterectomized women, it was suggested that withholding estrogen from women aged 50–59 years over a 10-year period in the US may have led to an excess mortality of between 18 000 and 91 000 women33. Because of the finding of benefit rather than harm in younger women in the WHI, which was consistent with the findings of older observational data, the focus of the most recent prospective MHT trials was to highlight the coronary effects of estrogen in younger women close to menopause. The three relevant trials are the Kronos Early Estrogen Prevention Study (KEEPS), the Early versus Late Intervention Trial with Estradiol (ELITE), and the Danish Osteoporosis Prevention Study (DOPS). KEEPS only studied 727 younger women within 3 years of menopause and compared CEE 0.45 mg with transdermal estradiol 0.05 mg and placebo for 4 years. Oral micronized progesterone 200 mg was used for 12 days each month. This relatively small study in younger women could not assess hard endpoints such as myocardial infarction but used the endpoints of carotid intima-media thickness (IMT) and coronary calcium. KEEPS failed to show any differences between estrogen and placebo34. A consideration for this null effect was that the women in this trial were selected for good cardiovascular health and were too healthy to show any differences over this relatively short interval of time. Indeed, while women were excluded from the trial if they had significant
Table 2 Consistency of data on the decreased mortality in younger women receiving estrogen in observational studies and randomized trials
Meta-analysis of observational studies27 Meta-analysis of randomized trials27 Bayesian meta-analysis27 WHI combined trials in 50–59-year-old women25 WHI 10-year data with CEE in 50–59-year-old women28 WHI 13-year data with CEE in 50–59-year-old women29 WHI 13-year-data with CEE/MPA in 50–59-year-old women29
Hazard ratio
95% confidence interval
0.78 0.73 0.72 0.70 0.73 0.78 0.88
0.69–0.90 0.52–0.96 0.62–0.82 0.51–0.96 0.53–1.0 0.59–1.03 0.70–1.1
WHI, Women’s Health Initiative; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate
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What the future holds for women after menopause coronary calcium at baseline, in women who had measureable coronary calcium at study onset, the women in the estrogen arms had less accumulation than those in the placebo arm, although this was not statistically significant. ELITE was more of a true test of the ‘timing hypothesis’, studying 643 women who were either within 6 years of menopause or 10 or more years from the time of menopause. Oral estradiol 1 mg was prescribed versus placebo and vaginal estrogen was used for 10 days monthly. The main endpoint, carotid IMT, was decreased after 6 years with oral estrogen in women within 6 years of menopause and was increased in the older women35. These preliminary data confirm the timing hypothesis showing that younger women benefit from estrogen by inhibiting atherosclerosis while older women fail to respond. In 2012, DOPS reported on 1006 women who, at the onset of menopause, were prospectively treated with estrogen (estradiol) alone or estrogen/progestogen (norethindrone acetate) versus no treatment for 10 years, with 16 years of follow-up36. A composite endpoint of mortality, hospitalization for congestive failure or myocardial infarction was significantly reduced in women on MHT and appeared to be more reduced, the younger the women were. There were also no adverse effects reported in this smaller group of women in terms of stroke, deep vein thrombosis or breast cancer36. In summary, the data we have at hand today (randomized trials including the WHI, meta-analyses, older observational studies, ELITE and DOPS) are consistent in showing a protective effect on atherosclerosis progression, coronary events and mortality in healthy young women who initiate therapy at the onset of menopause, but not in older women. The data are predominantly with the use of oral estrogen (CEE or estradiol) and the potential attenuating effects of MPA or any particular progestogen, while likely, remain uncertain at present.
WHERE WE WANT TO GO It first needs to be appreciated that there are risks in anything one does. As we suggest interventions to improve longevity and the quality of the lives of women, no action is totally risk-free. The absolute risks in a 50–59-year-old woman receiving CEE or CEE/MPA for 5–6 years according to data from the WHI is no more than five to six events/10 000 women29; this only pertains to data for breast cancer and thrombosis. The majority of effects are actually beneficial. While there remains some controversy over the ischemic stroke data in younger women in the WHI, the most recent cumulative data show no significant effect. On the other side of the coin, the therapeutic benefits in terms of reducing vasomotor symptoms and vaginal atrophy are in the range of 8000–9000/10 000 women37. Given that most effects in the 50–59-year-old group are beneficial, the magnitude of the hazard, for example the risk for breast cancer with CEE/MPA with longer-term therapy (not CEE alone), should be compared with some other naturally occurring annual risks. The risk of death in a motor vehicle accident is 1/6500; the risk
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Lobo of death from walking across the street is 1/48 500, and that from drowning or a fire is 1/88 000. The risk of having a car stolen is 1/100 and of having a house fire is 1/20038. There are even risks of myocardial infarction and mortality with taking supplemental calcium39. Indeed, for breast cancer, the relative risks are far greater if a woman has certain endogenous risks such as increased breast density or obesity than with the use of MHT40. As we move into the future, we are entering an era of personalized medicine. With sophisticated genetic and molecular tools, we are beginning to be able to catalogue the risks for breast cancer and CVD, for example, and know better how to intervene. At present, we already have a few tools. We know about probing for BRCA-1/2 genes to prevent breast and ovarian cancer41. The risk of breast cancer with MHT (both increased and decreased) has been associated with polymorphisms of the steroid receptor family42. Currently, however, genome-wide association studies have suggested that this interaction of various single nucleotide polymorphisms is too imprecise for wide application43. Estrogen receptor (ER) polymorphisms have also been identified regarding mortality outcomes with MHT44. Several polymorphisms affecting hepatic estrogen metabolism have been associated with thrombosis risk45,46. There may also be some association between ERα variants and severe depressive symptoms after menopause47. Perhaps the most knowledge we have in this area is in pharmacogenomics. Based again on genetic polymorphisms related to drug metabolism, we know what drug responses will be (increased or decreased) for a variety of drugs, such as warfarin, statins, and anti-platelet therapy48. Even the estrogenic response of increasing HDL cholesterol concentrations with oral estrogen is influenced by the particular genotype of ERα a woman has49. It can easily be envisioned that, in the near future, a simple blood test, coupled with family history, will provide a profile of future risks and responses to various medications including hormones. Thus, as we go into the future, assuring the health, quality of life and longevity of postmenopausal women will be based on preventative therapy. Menopause heralds an important opportunity to make appropriate adjustments to prevent diseases which begin to emerge 10 years later50. The path moving forward is then to initiate a comprehensive assessment including genetic and molecular tools, as they emerge, to define risks of disease and to intervene as needed. A prescription for healthy lifestyle and mental activities to prevent dementia will include specific exercises and diets depending on prediction models. If medical therapy is needed, pharmacogenomics will guide appropriate prescriptions and dose. As part of the choice for prevention therapies, MHT at the onset of menopause may be considered as part of this armamentarium50. In symptomatic women, the choice of MHT is clear and straightforward, as it is in those younger women who have a greater risk for osteoporotic fracture. In other women, assessments of risks and family history and other diagnostic tools may allow the clinician to consider MHT, specifically the use of estrogen for prevention. In younger women at the onset of menopause, there are
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What the future holds for women after menopause compelling observational and randomized, controlled trial data that estrogen decreases CVD and mortality. While some of the randomized, controlled trial data are subanalyses, as in the WHI, the consistency of the entire body of literature available to us, particularly with long-term data – women followed for 10 years or more, makes the argument more acceptable. It also needs to be appreciated that, apart from lifestyle changes, there is no other validated primary prevention therapy to prevent CVD in women50. Accepted therapies in men, such as statin and aspirin use, do not have the same effects in women50. Nevertheless, while the choice of the type of MHT is likely to be critical, there is no single product or regimen that can be endorsed. At present, we are not clear about types of estrogen, routes of administration or the best progestogen for women with a uterus. It is clear, however, that there are some additional risks of added progestogen in terms of breast cancer and thrombosis risks30. While there are some data suggesting that natural progesterone may be more beneficial, the data are still preliminary. Similarly, whether
Lobo the addition of a selective estrogen receptor modulator such as bazedoxifene may also be of benefit as an alternative to any progestogen is a potential51, but requires more study. Finally, it is not clear for how long therapy should be continued, particularly if symptoms are no longer the concern. There are some data that even short-term treatment at the onset of menopause may be of long-term benefit in preventing osteoporosis and cognitive decline52,53. More work is clearly needed in this area. In the final analysis, individualization is key; continuous ongoing assessment and the use of new diagnostic tools for efficacy and risks, and therapeutic adjustments as necessary, will insure the best welfare of postmenopausal women. Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
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Lobo 40. Santen RJ, Kronenberg HM, Melmed S, et al. Endocrine responsive cancer. In Williams Textbook of Endocrinology, 11th edn. Philadelphia: Saunders Elsevier, 2008:1764 41. Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med 2007; 357:154–62 42. Marie-Genica Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk. Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy. Int J Cancer 2010;126:2935–46 43. Hein R, Flesch-Janys D, Dahmen N, et al. A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication. Breast Cancer Res 2013;138:529–42 44. Ryan J, Canonico M, Carcaillon L, et al. Hormone treatment, estrogen receptor polymorphisms and mortality: a prospective cohort study. PLoS One 2012;7:e34112 45. Bouligand J, Cabaret O, Canonico M, et al. Effect of NFE2L2 genetic polymorphism on the association between oral estrogen therapy and the risk of venous thromboembolism in postmenopausal women. Clin Pharmacol Ther 2011;89:60–4 46. Canonico M, Bouaziz E, Carcaillon L, et al. Synergism between oral estrogen therapy and cytochrome P450 3A5*1 allele on the risk of venous thromboembolism among postmenopausal women. J Clin Endocrinol Metab 2008;93:3082–7 47. Ryan J, Ancelin ML. Polymorphisms of estrogen receptors and risk of depression: therapeutic implications. Drugs 2012; 72:1725–38 48. Yip VL, Pirmohamed M. Expanding role of pharmacogenomics in the management of cardiovascular disorders. Am J Cardiovasc Drugs 2013;13:151–62 49. Herrington DM, Howard TD, Hawkins GA, et al. Estrogenreceptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002;346:967–74 50. Lobo RA, Davis SR, De Villiers TJ, et al. Prevention of diseases after menopause. Climacteric 2014 June 27. Epub ahead of print 51. Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. Steroids 2014 June 14. Epub ahead of print 52. Bagger YZ, Tanko LB, Alexandersen P, et al. Two to three years of hormone replacement treatment in healthy women have longterm preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 2004;34:728–35 53. Bagger YZ, Tanko LB, Alexandersen P, et al. Early postmenopausal hormone therapy may prevent cognitive impairment later in life. Menopause 2005;12:12–17
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