© Springer International Publishing Switzerland 2017
Lubna Pal and Raja A. Sayegh (eds.)Essentials of Menopause Management10.1007/978-3-319-42451-4_22. Five Decades of Hormone Therapy Research: The Long, the Short, and the Inconclusive
(1)
Department of Obstetrics and Gynecology, Boston University Medical Center, Boston, MA, USA
(2)
Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon
Introduction
The symptom burden of midlife ovarian senescence and its impact on physical, emotional, and sexual well-being has long been perceived as disruptive to the personal, social, and professional aspirations of postmenopausal women. Low serum estrogen levels prevailing after menopause have also been associated with accelerated aging of tissues and organs, particularly the skeletal and cardiovascular systems [1, 2]. With the triumphant development of the oral contraceptive pill in 1960 [3], hope grew that biological challenges unique to the female post-reproductive years can too be conquered with the use of synthetic sex steroids. This hope was stoked as well by Wilson’s negative portrayal of the menopause as an “estrogen deficiency state” which “must be replaced” to avoid the “tragedy” and “decay” of menopause [4, 5]. Within a decade of Wilson’s influential assertions, the number of menopausal women who had taken up long-term estrogen therapy had soared [6]. Few years later, a significant body of observational data would demonstrate that such menopausal hormone therapy (MHT) is not only effective for control of troublesome symptoms but may also have benefits for the prevention of chronic diseases commonly associated with female aging [7–9]. The promise that a pill may improve life’s quality, and possibly its quantity, by increasing the odds of avoiding a heart attack or a hip fracture captured the attention of tens of millions of menopausal women whose ranks in the USA were growing rapidly as the baby boom generation matured. The promise of MHT also captured the attention of employers and the insurance industry who have a perennial interest in workforce wellness and of the pharmaceutical industry who saw a tremendous opportunity for growth. In 1991, the 102nd US Congress got involved as well, passing the Women’s Health Equity Act of 1991 [10]. While this act failed to become law, significant portions of it were ultimately included in the NIH Revitalization Act of 1993 which did become law, appropriating significant resources for women’s health research [11]. This confluence of public and private interests set the stage for accelerated investigation in menopausal medicine, including federally funded research developed and coordinated by the newly minted Office of Women’s Health at the National Institutes of Health (NIH). With cancer, heart disease, and osteoporosis as the leading causes of death, disability, and impaired quality of life in older women, the NIH launched in 1993 a landmark 15-year effort, the Women’s Health Initiative (WHI), to study these matters with scientific rigor. The role of MHT figured prominently in this effort with the inclusion of two long-term prospective randomized controlled trials (RCTs) – the WHI estrogen and progesterone (WHI-EP) and the WHI estrogen (WHI-E)-alone hormone trials. The publication of results in 2002 and 2004 of these WHI hormone trials formed a watershed event with worldwide changes in clinical practice and social attitudes toward acceptance of MHT. The WHI results inspired not only new and innovative MHT research but also a second look at existing MHT data that had predated WHI. This chapter summarizes five decades of MHT research in chronological order and highlights trends in clinical practice which swayed the research agenda and in turn were influenced by the results.
Pre-WHI
The Early Years of Estrogen Use
An isolate from the urine of pregnant mares, conjugated equine estrogen (CE) at an oral dose of 1.25 mg, had been approved for relief of menopausal symptoms by the Food and Drug Administration (FDA) in 1942, when proof of safety was the only requirement for approval [12]. CE’s efficacy had been widely accepted at the time but was only formally acknowledged by the FDA decades later in compliance with 1962 legislation after the thalidomide tragedy [13]. In high doses, estrogen therapy then had also found use in “androgen deprivation therapy” for men with metastatic prostate cancer and for the “endocrine priming” before chemotherapy in women with metastatic breast cancer [14, 15]. Interestingly, men on these high doses of estrogen were noted to have a lower burden of coronary atherosclerosis at autopsy [16, 17]. Animal studies in chicken and rabbits had also revealed that estrogen can reverse atherosclerosis and exert a favorable influence on serum levels of atherogenic cholesterol and lipoproteins [18]. Those observations offered a biological explanation for the known gender gap in heart disease incidence [19] and suggested the possibility that this leading cause of mortality in men can be prevented and treated with high doses of oral estrogen [20]. To investigate this possibility, middle-aged men with coronary artery disease (CAD) were enrolled in an estrogen arm of the “coronary drug project,” but excess mortality from thromboembolic incidents led to the abandonment of this effort [21–23]. The use of high-dose estrogen in metastatic prostate and breast cancer patients was similarly abandoned when newer therapeutic alternatives became available for these conditions in the 1970s.
Coronary Benefits and Stroke Risks of Postmenopausal Estrogen
The concept of cardioprotection by estrogen was revived in the 1970s in postmenopausal women, many of whom had started taking CE a decade earlier to combat not only the symptoms but also the social and cultural stigma of menopause propagated by the influential New York Times best seller, “Feminine Forever” [5]. At that time, few small observational studies had suggested a 30–50 % reduction in risk of CAD, lower death rates from stroke and heart attacks, and reductions in all-cause mortality among postmenopausal estrogen users compared to nonusers [24–27]. Concurrent serum lipid studies had also revealed significant estrogen-induced reductions in total cholesterol levels and increases in high-density cholesterol levels [28, 29]. These desirable effects of estrogen on serum lipids were advanced as an important, but not singular, mechanism for the observed cardioprotective effects of estrogen that purportedly required sustained intake of estrogen to maintain. These impressions would later be confirmed by one of the largest and longest running observational studies of that era, the Nurses’ Health Study (NHS), which in 1976 had started collecting detailed information on a cohort of 121,700 nurses to determine risk factors for major chronic diseases. In their first report on MHT in 1985, 32,317 postmenopausal women had been followed for an average 3.5 years, and those on estrogen had a 50 % lower risk of CAD [8]. One third of the estrogen users in this cohort were taking 1.25 mg CE daily, while others were using lower doses of estrogen. In 1991, a second NHS report affirmed this finding in a larger cohort of 48,470 postmenopausal women that had accrued an average follow-up period of 10 years [30]. In addition to a decreased incidence of CAD, this second NHS report had also found a trend toward reduction in all-cause mortality with current postmenopausal estrogen use. The cardioprotective benefits of oral estrogen were observed even in older women and in women with established CAD [31] bolstering the preponderance of evidence from many earlier and smaller observational studies which had come to a similar conclusion [32]. The one notable exception of that era was the Framingham study which, contrary to the bulk of the existing data, had found an increased coronary risk associated with menopausal estrogen therapy [33].
In contradistinction to the coronary benefits of estrogen, the Nurses’ Health and Framingham studies both found trends toward increased risk of ischemic stroke among estrogen users, which in the case of the NHS cohort did not reach statistical significance [32]. As to the Framingham study, the cohort of postmenopausal women was much smaller than the NHS cohort, with a higher percentage of older women, smokers, and 1.25-mg CE users [33]. The then controversial issue of an increased stroke risk with estrogen use was compounded by observational reports starting in 1996 of increased venous thromboembolism (VTE) risk in association with MHT use [34]. However, these concerns were inconsistent with other observational studies and meta-analyses which demonstrated either no increase [35, 36] or even a decrease in stroke risk with estrogen use [37–40]. Furthermore, the promise of neuroprotection by estrogen gained impetus with the reporting of a 30 % reduction in risk of cognitive impairment and Alzheimer’s disease (AD) with MHT [41, 42]. Given that stroke was (and remains) a leading cause of mortality in aging women and given that nonfatal stroke is a major risk factor for cognitive decline in postmenopausal women, the idea of using estrogen for secondary prevention of stroke and cognitive decline emerged in the late 1990s and was tested in two NIH-sponsored RCTs: Women’s Estrogen for Stroke Trial (WEST) and the cognitive substudy of the Heart and Estrogen/Progestin Replacement Study (HERS-Cog).
The WEST was a multicenter secondary prevention stroke trial that randomized 664 women (mean age 71), within 3 months of an incident stroke or ischemic attack, to receive either placebo or MHT [43]. The hormone regimen consisted of 1 mg oral estradiol daily along with cyclic medroxyprogesterone acetate (MPA) for non-hysterectomized women. Overall, there was no significant reduction in the incidence of recurrent stroke with MHT use after a mean follow-up duration of 2.8 years. Concerningly and unexpectedly, the estrogen users had a higher incidence of a fatal second stroke; furthermore, neurologic and functional deficits were worse among estrogen users who experienced a recurrent nonfatal stroke. There was a tendency toward more recurrent events in the first 6 months after randomization among estrogen users, although statistical significance was not reached for all these outcomes. As to those estrogen users who did not have a recurrent stroke during the course of this trial, cognitive scores were no better (or worse) than for those on placebo [44]. In the HERS-Cog trial (a substudy of the larger HERS trial to be discussed later), 1000 cognitively intact older postmenopausal women with established CAD (a known risk factor for stroke) were randomized to receive either placebo or continuous combined 0.625 mg CE with 5 mg MPA for 4 years. Those on MHT did not score any better or worse on cognitive tests after 4 years of therapy compared to women assigned to placebo [45]. Finally, in a randomized trial of estrogen in 120 postmenopausal women with established early AD, neither 0.625 mg CE nor 1.25 mg CE proved any better than placebo in halting or slowing disease progression, and in some instances the condition even got worse on estrogen [46]. What became clear after these trials was that conventional oral MHT is not beneficial for secondary prevention of stroke and cognitive decline in older postmenopausal women. However, the biological plausibility of neuroprotection by estrogen suggested by in vitro and animal studies [47] continued to fuel a hope that MHT will prove beneficial for neurocognitive processes. The scientific world and community looked forward to the results of the primary prevention trials which were already under way, including the WHI Memory Study (WHIMS), which will be discussed later.
The Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial
Five decades after the introduction of CE in clinical practice, the widely acknowledged need for comprehensive RCTs to resolve lingering controversies and uncertainties materialized with the launch of the NIH-sponsored PEPI trial in 1991. One of those leading controversies of the time was the association between unopposed CE use and increased endometrial cancer risk which had emerged in 1975 [48]. While small-scale European and US studies had shown that this risk can be eliminated with the adjuvant use of a progestin [49, 50], such use remained controversial and unpopular in the USA due to the physical side effects of added progestin use (breast tenderness and resumption of periods) and concerns about progestin’s lipid attenuation benefits [51]. This fact is reflected in the reality that only 12 % of MHT users in the 1991 NHS report were using progestins! This changed significantly after PEPI.
In the PEPI trial, 800 and 75 newly menopausal women with and without a uterus were recruited to participate in a 3-year RCT of MHT. The mean age of participants was 56 years and none was more than 10 years postmenopausal. The study had a placebo arm and four MHT arms that utilized an identical standard 0.625 CE dose, reflecting the US market dominance of this product, but differed in progesterone type and regimens. The four MHT regimens included CE alone, CE plus oral micronized progesterone for 10 days every month, CE plus oral MPA taken continuously at a dose of 2.5 mg daily, and CE plus oral MPA taken cyclically at a dose of 5 mg for 10 days each month. All the study medications were donated by the manufacturing pharmaceutical companies. One of the limitations of the PEPI trial which emerged after the fact was that blinding was suboptimal due to estrogen’s obvious physical effects. Adherence rates to assigned therapy were also suboptimal because symptomatic women who received placebo could not tolerate staying on for 3 years knowing that effective therapy was available. High dropout rates also occurred in some treatment arms due to bleeding and concerns about endometrial cancer risk. Adherent analyses were used to adjust for these limitations, raising concerns about introducing a selection bias [52]. Those limitations notwithstanding, the PEPI trial results remain groundbreaking and influential, confirming the efficacy of CE for menopausal symptoms, the effectiveness of progestins for endometrial protection, and the beneficial effects of standard dose hormones on preserving BMD [53, 54]. In addition, hope for cognitive protections was raised based on self-reported improvements in memory and cognition among estrogen users [55]. Most importantly the benefits of CE and to a lesser extent CE and progestin regimen on serum lipids, fibrinogen levels, and carbohydrate metabolism were now firmly established in a RCT [56]. While cyclic natural progesterone was found to be the least attenuating to CE effects on serum lipids, the use of continuous daily MPA with CE eventually promoted amenorrhea, a major advantage in the effort to enhance long-term compliance with MHT [57]. This so-called continuous combined estrogen/progestin (CCEP) regimen gained FDA approval for treatment of menopausal symptoms and osteoporosis prevention in 1995 and became the dominant form of MHT for non-hysterectomized women in the USA. It was also the regimen of choice which would be tested subsequently in landmark RCTs for primary and secondary prevention of CAD.
Postmenopausal Estrogen Use and Public Health
With CAD as the leading cause of death and disability among postmenopausal women, the near-consistent and biologically plausible evidence of significant cardioprotection by postmenopausal estrogen overshadowed other concerns. Ultimately, the argument for a public health benefit of long-term estrogen was so compelling that the second report of the Adult Treatment Panel of the National Cholesterol Education Program (ATP-NCEP) stated that estrogen can be considered as a first-line therapy for postmenopausal women with elevated cholesterol levels [58, 59]. In addition, a major physician group, the American College of Physicians (ACP), stated in 1992 that “women who have CAD or who are at increased risk for CAD are likely to benefit from hormone therapy” [60]. This recommendation was strong for women who have had a hysterectomy and were therefore able to use unopposed estrogen without concern for endometrial cancer risk. As to MHT use for non-hysterectomized women, ACP’s recommendation was cautious given progestin’s known attenuating effects on estrogen’s lipid benefits and possibly its cardioprotective benefits. With the supportive PEPI trial findings coming shortly thereafter, the emphasis of postmenopausal hormonal therapy had clearly moved beyond quality-of-life issues (hot flash control, preservation of sexual function, relief of vulvovaginal atrophy, and improved sense of well-being). The focus in 1995 was on preventing heart attacks and reducing cardiovascular mortality for an entire population of postmenopausal women. An editorial by the first female director of NIH accompanying the PEPI publication expressed optimism that perhaps the “opportunity to halt womankind’s vulnerability to heart disease after menopause may be at hand” [61]. Yet, as with the ACP recommendation 3 years earlier, there was careful acknowledgment by the author that the final answer regarding the efficacy of hormones for primary and secondary prevention of heart disease would have to await the results of much larger and longer RCTs in which hard clinical end points were being assessed. This left the door open to the possibility that recommendations may evolve accordingly.
National surveys conducted in the early to mid-1990s showed peaking prevalence of MHT use among middle-aged women, yet they also showed a persistently low prevalence of sustained long-term use believed necessary for the maintenance of cardiovascular and skeletal benefits. In one of these surveys conducted in 1995, 38 % of 50–74 years old women were using MHT, but only 20 % had used it for 5 years or more [62]. Another 1995 survey found MHT use to be rising among postmenopausal physicians, including older physicians, which presaged well for a continuing rise in MHT acceptability among the general public [63]. Other surveys revealed a significant regional variability in prevalence of MHT use which was highest among women in the South and West and lowest in the Northeast of the USA [64, 65]. Additional determinants of the prevalence of MHT use included hysterectomy status [66], the nature of counseling, and the specialty of those counseling menopausal women [67]. Perhaps most revealingly however were surveys that showed that more than half of the women who started MHT stopped it within 2 years of initiation either because of undesirable side effects or concerns regarding increased risk of stroke, breast cancer, and endometrial cancer [68, 69].
Skeletal Benefits of Postmenopausal Estrogen and the Push for Lower Doses
By the early 1980s, a number of observational and randomized trials had shown postmenopausal estrogen use to be associated with preservation of bone mineral density (BMD) and skeletal protections against osteoporotic fractures, a major contributor to disability and morbidity in the aging populations [9, 70]. Furthermore, 0.625 mg of CE was found to be equally effective as higher CE doses for menopausal symptom relief and for BMD preservation [71]. In 1986, CE became the first FDA-approved antiresorptive therapy for the prevention of postmenopausal osteoporosis [13, 72]. Recognizing the tremendous marketplace potential of this development, rival pharmaceutical companies launched efforts to introduce synthetic equivalents to the marketed CE, but those efforts failed as the chemical complexity of CE was revealed [73]. While 0.625 mg CE became the standard MHT dose and maintained its market dominance in the USA, compliance with long-term use believed necessary for the realization of its presumed skeletal and cardioprotective benefits remained suboptimal for reasons discussed earlier. In an effort to overcome barriers against wider utilization and long-term compliance, industry-sponsored randomized trials were launched, demonstrating that CE doses under 0.625 mg remained efficacious for relief of hot flash and vulvovaginal atrophy, preserved BMD, and induced favorable serum lipid changes, albeit less robustly than 0.625 mg of CE [74, 75]. In lower doses, oral estrogen had a lesser impact on the triglyceride (TG) level, which was found to be an independent marker of cardiovascular risk in women in the Framingham study [76]. Around the same time, natural estradiol and the means to deliver it transdermally via patch were also introduced, and short-term trials with the transdermal estradiol (TDE) found it comparable to oral CE for symptom relief and BMD preservation [77, 78]. While TDE was less effective in comparison to oral estrogen as far as cholesterol benefits were concerned, it had the advantage of promoting a more physiologic estrogenic milieu and avoided the “first-pass” liver effects implicated in much of estrogen’s undesired prothrombotic effects and stroke risk [79].
While TDE use was becoming increasingly popular in Europe, greater than 80 % of estrogen users in the USA continued to use oral conventional doses of CE due to its perceived benefits on hard clinical end points (fractures and heart attacks) and not just on surrogate markers of risk (BMD and serum lipid levels). This clinical reality would play an important role in the design of the NIH-sponsored randomized MHT trials that launched in the early 1990s. No transdermal or low-dose estrogen products were tested neither in the PEPI nor the WHI trials. These low-dose oral and transdermal products which had gained FDA approval for menopausal symptom relief and osteoporosis prevention in this era would however play important clinical and research roles in the aftermath of WHI.
Postmenopausal Estrogen Use and the Secondary Prevention Trials
Contemporaneously with the PEPI trial, a sizable industry-sponsored multicenter RCT was launched to test the hypothesis generated by earlier observational studies that CE therapy was beneficial not just for primary prevention but also for secondary prevention in women who already have CAD. The Heart and Estrogen/Progestin Replacement Study (HERS) recruited 2700 older non-hysterectomized women (average age 67 years) with established CAD, randomized them to CCEP or placebo, followed them for over 6 years, and measured well-defined clinical end points as well as surrogate markers of cardiovascular risk. The hormone therapy regimen which was chosen for HERS had already been proven to protect the endometrium and promote amenorrhea, factors that would help maximize long-term compliance with assigned therapy. The results of HERS published in 1998 contradicted the observational evidence, finding an increase in risk of cardiovascular events in the first year of therapy, a decrease in events in subsequent years, and no net overall cardiovascular benefit over the 6.8 year duration of the study [80–82].
In addition to HERS, the secondary prevention of CAD and stroke was investigated in a number of NIH-sponsored angiographic RCTs [83–85]. Women recruited for these 2–3-year trials were comparable in age and cardiac history to those in HERS, and many of them were on lipid-lowering therapies. Conventional oral doses of CE and natural estradiol with and without progestins neither slowed the progression of coronary artery stenosis nor reversed it, despite inducing desirable and expected changes in serum lipids. These findings were consistent with the HERS clinical findings, but unlike HERS there was no evidence of excess risk in the early months of hormone use in the angiographic trials. While this may be due to lack of study power, the concurrent statin use by the majority of women in those trials may have protected against early events. This theory was tested in a subgroup reanalysis of the HERS data, finding no increased risk of early adverse events among the subgroup of CCEP users who were taking statins [86].
Taken collectively, the clinical and angiographic secondary prevention trials indicated that commonly prescribed oral estrogen doses with or without progestins are not helpful in women with established CAD in the sixth and seventh decade of life. While the hope for secondary prevention of CAD by estrogen faded, hope persisted that estrogen might be proven beneficial for primary prevention of CAD. This hope was kept alive by the results of the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), a 2-year randomized prospective trial which found that standard dose oral estradiol slowed the progression of subclinical carotid atherosclerosis in younger postmenopausal women with high cholesterol levels, particularly those of them who were not on statins [87]. This however was a surrogate end point study, and it would be few more years before a number of RCTs with hard clinical end points could weigh in on the subject matter. In the USA, the WHI hormonal trials had been underway since 1998. Overseas, the Women’s International Study of long Duration Oestrogen after Menopause (WISDOM) was also afoot, with plans to test the effects of CE and CCEP on multiple primary and secondary outcomes in a younger cohort of menopausal women in the UK, Australia, and New Zealand. The Danish Osteoporosis Prevention Study (DOPS), a-20 year effort to test the fracture reduction benefits of natural oral estradiol in newly menopausal women, had been in progress as well since 1990, with plans to report on cardiovascular disease as a secondary outcome.
The Women’s Health Initiative (WHI)
Summary of the Trial Design
The WHI, a large and multifaceted NIH effort, was launched the same year as PEPI, to evaluate the most common causes of death, disability, and poor quality of life in postmenopausal women, namely, cardiovascular disease, cancer, and osteoporosis. The effort consisted of an observational cohort and two hormone trials, which altogether involved 161,808 generally healthy postmenopausal women [88]. The hormone trials of the WHI were designed to test the effects of MHT on heart disease, fractures, and colorectal and breast cancer. Based on existing knowledge, hormones were expected to decrease CAD risk and increase breast cancer risk, and those were the two primary outcomes for which the trials were designed and powered. Skeletal fractures, other cancers, and total mortality were secondary outcome measures in the WHI. Over 27000 women age 50–79 were enrolled at 40 clinical centers nationwide in the two WHI hormone RCTs, one for hysterectomized women (WHI-E trial that compared 0.625 oral CE against placebo) and the other for women with an intact uterus (WHI-EP trial in which CCEP was tested against placebo). Wyeth-Ayerst Research Laboratories (Philadelphia, PA), the maker of both hormonal products, agreed to donate the active and placebo pills for the effort. It is noteworthy that these were the first large-scale menopause trials to enroll significant proportions of nonwhite minority women in an effort to ensure that results would be generalizable to the population at large.
Just like PEPI and HERS, the choice of hormonal regimen utilized in the WHI hormone trials reflected prevalent prescribing practices in the USA at the time. Unlike PEPI however, WHI participants were older with a mean age of 64, and only a third of them were within 10 years of menopause. A mere 3.5 % of WHI participants were between 50 and 54 years, the age at which women often decide whether to initiate HT or not for symptom management. The choice of mostly asymptomatic postmenopausal women would help ensure better blinding and reduce dropout rates which had plagued PEPI. Most participants in WHI (70 %) were also overweight or obese with a mean BMI of 30 kg/m2, and nearly 40 % were former smokers. The inclusion of many women with these CAD risk factors was justifiable for trials whose intent was to evaluate estrogen’s role in primary prevention of CAD and in light of existing favorable observational and biomarker studies [31, 56]. One should remember here that the HERS and the angiographic trial findings discussed earlier had not been known yet when design and recruitment for the WHI clinical trials got under way.
Placing WHI Core Findings in Perspective
WHI-EP trial was planned to run until 2005, but the findings of an overall increase in risks of coronary heart disease, stroke, pulmonary embolism, and breast cancer relating to hormone use led to its premature termination in 2002 after an average follow-up period of 5.2 years [89]. While CCEP users experienced fewer hip fractures and colon cancers (secondary outcomes), the monitoring agency felt that the net risk of harm of MHT was larger than the net benefit and stopped the study. However, longitudinal follow-up of the WHI-EP cohort continued until 2010 yielding important information which will be discussed later. WHI-E kept going for another 2 years when it too was stopped prematurely. After an average 6.8 years of oral CE use, the only benefit was a reduced risk of hip and other fractures [90], a secondary outcome for the study. While reassuringly, there was no increased risk of breast cancer or coronary heart disease with the use of CE alone; no obvious cardioprotective benefit was apparent either. Similar to the WHI-EP trial, an increased risk of stroke and deep vein thrombosis (secondary outcomes) was evident in the hormone, compared to placebo users.
The 30 % increase risk of ischemic stroke (50 % increase after adjusting for nonadherence) found in association with HT use in both WHI-EP and WHI-E would soon be compounded by negative cognitive findings from the WHI Memory Study, or WHIMS [91, 92]. This substudy of WHI involved over 7000 cognitively intact subjects aged 65–79 years from both WHI trials who were followed for approximately 5 years. A 76 % increase in risk of cognitive decline and dementia was found among HT users in WHIMS, but it was not clear to what extent this increased risk of cognitive decline was mediated by stroke. However, it became clear after WHI and WHIMS, and the earlier WEST and HERS-Cog trials, that the use of conventional oral HT for primary or secondary prevention of cognitive decline in older postmenopausal women is in the least ineffective and possibly associated with increased stroke risk and accelerated cognitive decline. While these findings were somewhat disappointing, they were not unique to conventional oral MHT. Increasingly, popular alternatives for skeletal protection and menopause management, e.g., selective estrogen receptor modulators (SERMs) and tibolone, would soon be tested in industry-sponsored RCTs and would also be found to be associated with increased stroke and thromboembolism risks [93, 94].
Revelations from the WHI’s hormonal trials and its substudies would have profound, lasting, and far-reaching influence on social attitudes toward MHT and on governmental oversight of existing and new women’s health products. This transpired despite the many shortcomings of those trials which became apparent only in hindsight, including the older age and advanced menopausal state of the enrollees, the low adherence and high dropout rates, the inadequate power for the stroke outcomes, and the fact that only a single type and dose of oral estrogen and one oral progestin were tested (compared to the wide variety of hormonal products and regimen in existence at the time in the USA and worldwide). The WHI trial findings would also trigger a massive revisionist effort to try to understand the reason behind the discordance between WHI and observational studies regarding cardioprotection. In the process, clinical practice would change, new hypothesis would be generated and tested, and the quest for optimal post-reproductive female health and well-being would march on.
In contrast to the discordance on coronary artery disease, the WHI results were concordant with earlier observational and randomized trial evidence regarding estrogen’s osteoporosis prevention and fracture reduction benefits. WHI-E and WHI-EP were indeed the first primary prevention trials in menopause research to demonstrate that skeletal protection extended to black women and that race/ethnicity did not modify the treatment effect [89, 90, 95]. Prior to WHI, the HERS secondary prevention trial did observe BMD improvements with estrogen use in older women not selected for osteoporosis but could not demonstrate a fracture reduction efficacy, possibly because of its much smaller cohort size [96]. From a public health point of view, this demonstration of success in primary prevention of osteoporotic fractures in a randomized trial with hard clinical end points was remarkable. Yet the requisite sustained intake of conventional MHT for fracture prevention had, by virtue of the same trials, become less palatable due to the increased CAD and breast cancer risks among WHI-EP subjects and the increased stroke risk among WHI-E and WHI-EP participants. Furthermore, the increasing focus on treatment-related risk/benefit calculus had also extended well beyond the realm of hormone therapy. Contemporaneously, national guidelines for osteoporosis prevention and fracture reduction had evolved since the 1980s, emphasizing calcium, vitamin D, and smoking cessation for primary prevention [97]. Pharmacotherapy was no longer advisable except in women where the calculated 10-year hip fracture risk exceeded 3 % or the 10-year all-site fracture risk exceeded 20 % [97]. Although estrogen remained FDA approved for osteoporosis prevention, bisphosphonates which had been approved in 1995 had now replaced estrogen as first-line agents for fracture prevention in at-risk women in both the USA, Europe and most of the world [98, 99]. An important exception to this paradigm shift is women experiencing premature menopause, be it natural or iatrogenic, where WHI findings are not relevant. In these women there is evidence and consensus that, barring any contraindications, conventional dose MHT is advisable until the usual age of menopause, to help preempt the negative skeletal and cardiovascular impact of premature loss of ovarian endocrine function [100].
Post WHI
A Changed and Changing Landscape
With the release of the WHI findings and the consequent mandate by the FDA for a black box warning on all E and EP products sold in the USA [101], a new day had dawned on the field with dramatic decline in HT use in the USA and worldwide [102–106]. A case in point is the drop in number of CE and CCEP prescriptions in the USA from 61 million in 2001 to 21 million in 2004 [102, 105]. Additional dramatic effects were manifest with the abrupt termination of several long-term randomized controlled MHT trials. One of the notable casualties was the WISDOM trial which was halted before any meaningful accrual had occurred [107]. Had WISDOM been allowed to continue, it could have provided invaluable information about the coronary risks and benefits of the same hormones used in WHI trials, but in a cohort of younger women. Clinically, the doubts raised by WHI about cardioprotection by estrogen and the possibility of increased coronary risk with EP further undermined the main public health argument for the cardioprotective benefits of long-term MHT. This argument had in fact been steadily eroding with a 50 % decline in CAD mortality between 1980 and 2000, mostly attributed to improved diagnostic and therapeutic interventions for CAD and to widespread societal change in attitudes and behavior toward modifiable risk factors, e.g., smoking, hypertension, and dietary cholesterol [108, 109]. With this as a backdrop, the revelations from WHI drove a large number of women and their providers to abandon MHT not only for prevention of chronic disease but also for symptom relief, despite their superior efficacy and continued FDA approval for management of menopausal symptoms. This flight away from HT after WHI was facilitated as well by the availability of alternative less stigmatized pharmacologic options for symptom management and for the prevention of chronic diseases (e.g., statins, bisphosphonates, SERMs, and SSRIs), although these too were later proven not to be without risk [93, 110–112].
In this changing landscape, a new emphasis emerged post WHI that focused on individualized therapy to improve the quality of life for symptomatic menopausal women [113]. If the old paradigm of postmenopausal MHT use was “more is better,” the mantra after WHI became “less is more.” But the questions begging for answers persisted; are those low-dose, short-term, FDA-approved hormones absolutely safe? Yes, they are effective hot flash therapies and they might improve sleep [75, 114, 115], but women who use them do not want to lose sleep worrying about their long-term risk of stroke, heart attack, cognitive decline, and breast cancer; similarly, prescribing providers need not lose sleep either, worrying about potential for litigation. The clinical agenda after WHI thus focused on developing evidence-based guidelines to better define and quantify the magnitude of MHT risks for the real-life users (i.e., symptomatic young perimenopausal and early menopausal women) and to aid in the individualized assessment, counseling, and treatment of the symptomatic menopausal woman. The research agenda post WHI was similarly dominated by clinical concerns and fell into four main categories: (1) efforts to reconcile the discordance between randomized trials and observational studies, (2) mining of new data from ongoing observational studies both in the USA and internationally, (3) randomized controlled trials to test hypothesis generated from 1 to 2 using low-dose HT doses and non-WHI regimen, and (4) novel basic and clinical research seeking to find effective safe alternatives for management of symptomatic menopausal women. What follows is a summary of these research efforts as they relate to these main clinical concerns.
Menopausal Hormone Therapy and Coronary Risk
Reconciling the Discordance Between Observational and Experimental Studies
Understanding the root cause of discordance regarding cardioprotection between WHI hormone trial data and results of earlier observational studies required a revisit of the methodologies and reevaluation of the participants in these studies. Upon review and application of new statistical tools and reanalyses, two factors emerged as important contributors to the inadvertent exaggeration of estrogen’s benefits in the observational trials. These were (1) a “healthy user” selection bias (80 % of estrogen users in NHS were newly menopausal symptomatic women) and (2) a selection bias caused by the inefficient accounting for early postexposure risk [116–118]. In this latter situation, an adverse event shortly after exposure to MHT often reduces the likelihood that those afflicted are available and counted at the time of the biennial questionnaire. A case in point is WHI’s own observational study (WHI-OS) which had in fact initially found decreased coronary risk among current EP users, but on reanalysis and inclusion of those who had suffered early postexposure coronary events, no cardioprotective benefit was found among current EP users [118]. As to the “healthy user” effect, a stratified subset reanalysis of the WHI-E and WHI-EP cohorts revealed menopausal age at initiation of HT to be an important determinant of coronary risk. Women who were less than 10 years postmenopausal at randomization actually demonstrated decreased CAD risk with MHT use. In contrast, those who were more than 20 years postmenopausal at randomization demonstrated an increased risk of CAD with hormone use [119]. This impression was also corroborated by WHI-OS which found similar risk patterns based on menopausal age at initiation of MHT [120]. Given the small number of subjects under 60 in the WHI, statistical power for the age-stratified analysis was lacking, and controversy persisted whether initiation of hormones at a younger menopausal age is associated with a real protective benefit, or just no risk [121]. Nevertheless, the “timing hypothesis” emerged as a new concept in coronary protection by estrogen.
Emergence of the “Timing Hypothesis”
The timing hypothesis stipulates that initiation of estrogens closer to the time of onset of menopause may protect the coronaries not only via reductions in serum lipids but also thru direct vascular effects that require a healthy coronary endothelium. By the same argument, older postmenopausal women who are more than 10 years postmenopausal are more likely to have coronary endothelium that is compromised by unstable atherosclerotic plaques. As such, older women will either derive no coronary benefits from estrogen or may even accrue an early risk due to acute thrombosis and rupture of unstable atherosclerotic plaques promoted by prothrombotic and pro-inflammatory effects of oral estrogen. The theory is supported by strong evidence from primate research [122] and by the results of the EPAT trial mentioned earlier where oral 17-beta estradiol intake for 2 years did slow the progression of subclinical carotid atherosclerosis in a cohort of young and healthy postmenopausal women with elevated cholesterol levels [87]. The timing hypothesis would also explain the HERS trial results and many of the angiographic studies discussed earlier that identified no benefits and possibly an increase in early post-exposure risk; notably, all of these studies recruited predominantly older women who were more than 10 years postmenopausal.
Experimental Testing of the Timing Hypothesis
The timing hypothesis would be tested prospectively in two new RCTs after the WHI. The Kronos Early Estrogen and Progesterone Study (KEEPS) was a privately funded multicenter placebo-controlled RCT of 727 non-hysterectomized women [123, 124]. The average age of the cohort was 52.7 years, and all were within 3 years of the onset of menopause. Study subjects were randomized to a placebo arm, or one of two low-dose estrogen arms: oral CE 0.45 mg and 50 μg/day TDE. Uterine protection in the hormone users was achieved with cyclic oral natural progesterone, 100 mg/day for 10 days each month. The trial was not large or long enough to allow reliable use of clinical outcomes; surrogate markers of cardiovascular risk (coronary artery calcium [CAC] and carotid intimal-medial thickness [CIMT]) were measured instead as primary outcomes of interest over the 4-year study duration. Following 4 years of hormone intervention, there was no difference between hormone therapy groups and placebo in the progression of subclinical atherosclerosis reflected by CAC score and CIMT [123]. Predictably, low-dose oral CE was associated with reduced LDL-C and increased HDL-C and TG levels, while low-dose TDE was neutral on lipids. Both hormonal treatment regimens were effective for vasomotor symptom relief. Thus, while KEEPS did not support the timing hypothesis, the minimal progression of subclinical atherosclerosis observed in all three study arms provided a measure of reassurance to newly menopausal short-term users of low-dose HT formulations.
The Early vs. Late Intervention Trial with Estrogen, or ELITE, was the second trial that explored the timing hypothesis, again with a focus on CIMT as a surrogate measure of cardiovascular risk. A longer 6-year RCT compared to KEEPS, conventional dose oral estradiol therapy was utilized in ELITE that recruited 643 women who were either less than 6 years postmenopausal (mean age 55) or more than 10 years postmenopausal (mean age 65). Each subgroup was randomized to placebo vs. 1 mg of oral estradiol; cyclic vaginal micronized progesterone gel was utilized for endometrial protection for the hormone users [125]. In a recent preliminary report from ELITE, oral estradiol therapy in the younger subgroup of women appeared to be associated with a slower progression of subclinical atherosclerosis as reflected by CIMT, compared to placebo; notably, no such difference was seen among the older cohort of estradiol users [126].
Additional support for the timing hypothesis has come from post hoc analysis of the long-running Danish Osteoporosis Prevention Study (DOPS) which had been terminated in the wake of WHI. By then, the cohort of nearly 1006 newly menopausal women enrolled within 2 years of their last period had completed 10 years of randomized treatment. 504 subjects received no active hormonal therapy and 502 subjects received 2 mg daily oral estradiol. Those taking estradiol who had an intact uterus also received oral 1 mg norethisterone acetate for 10 days each month. After 10 years of randomized treatment and an additional 6-year post cessation follow-up of the cohort, a 50 % lower risk of mortality, heart failure, and myocardial infarctions was reported among subjects randomized to hormone therapy compared to those on placebo [127].
Menopausal Hormone Therapy and Breast Cancer Risk
The Origins and Evolution of the Association
With serious doubts cast by WHI over the cardioprotective benefits of estrogen, the perennial and decades-old debate about the association between HT and breast cancer was rekindled, along with a sharpened focus on the role of progestins in this association. Starting in the 1970s, various observational studies, including the NHS, had reported an increased risk of breast cancer among long-term MHT users, but the nature and strength of this association had remained controversial [128]. Some felt the risk to be overstated due to increased utilization of screening mammography in women on HT (screening bias) resulting in discovery of occult, low-grade, node-negative, estrogen receptor-positive tumors with no increase in breast cancer-related mortality [129, 130]. Others felt the risk to be understated due to a selection bias whereby women with early onset surgical menopause, known to have a lower baseline risk of breast cancer, were overrepresented in the MHT cohorts [131].
The argument for a causative association between MHT and breast cancer received a boost from the PEPI randomized controlled trial where an increase in mammographic density was noted in some subjects on combination EP regimen [132]. This also generated concern about reduced sensitivity of screening mammography in women on HT [133]. Biological plausibility of an association between estrogen and breast cancer was further supported by trials demonstrating decreased breast cancer risk among users of the SERMs: tamoxifen and raloxifene [134, 135]. The case for causation was further strengthened with the release of WHI-EP findings showing a 30 % higher breast cancer risk among CCEP users [89]. Given the screening mandates of the WHI, the “screening bias” argument could no longer be invoked for WHI-EP. The average time to harm in this trial was 5.6 years, and the breast cancers were more advanced with more lymph node involvement and associated with higher mortality rates than the breast cancers occurring in women on placebo. This increased risk of, and mortality from, breast cancer would be later confirmed among CCEP users in WHI-OS [136], corroborating the randomized trial findings. It is not entirely clear however if the more advanced breast cancers in CCEP users were due to biologically more aggressive higher-grade tumors, or consequent to a delayed diagnosis attributable to reduced sensitivity of screening mammography, or both. It also remains a matter of debate whether the higher mortality from breast cancer in CCEP users was due to a higher incidence or higher case fatality rate or both. It is interesting to note that the extended follow-up of the WHI-EP cohort after the trial ended found that the MHT-related breast cancer risk persisted for many years after cessation of therapy [137]. This was discordant with the results of the majority of older and newer observational studies and meta-analyses which had shown declining breast cancer risk among past users of hormone therapy and vanishing risk after 5 years of MHT cessation [138]. It is also at odds with population data showing a worldwide decline in incidence of breast cancer with the global decline in MHT use in the early years after WHI [139–143].
Estrogen, the “Gap Theory,” and Breast Cancer
In contrast to WHI-EP, the WHI-E trial found no increase in breast cancer risk after 6 years of unopposed CE use and an actual decrease in the incidence and mortality from breast cancer in the 5-year post study follow-up of the cohort [144, 145]. These findings are at first glance discordant with most of the older observational studies, including NHS where unopposed CE was similarly the predominant form of MHT used. On stratified reanalysis of the NHS cohort however, an increased risk of breast cancer was only noted after 15–20 years of estrogen-alone use [146], reconciling it to some degree with findings of the much shorter WHI-E trial. WHI-E findings remain discordant however with those of two very large observational studies which commenced in the 1990s. The Million Women Study (MWS) undertaken in the UK and the French Etude Epidemiologique aupres de femmes de l’Education National (E3N) study had both found increased breast cancer risk to be associated not only with EP use but also, and to a lesser degree, with unopposed estrogen use as well [147, 148]. Important methodological differences between these newer observational studies and the WHI-E study may account at least in part for this discordance. This includes higher obesity rates in the WHI trial cohorts, higher prevalence of natural transdermal estrogen use in Europe, higher prevalence of MHT use prior to study enrollment in the observational trials, and a younger age at initiation of MHT in the observational studies. Regarding the latter, it is noteworthy that all three newer observational studies (E3N, MWS, and WHI-OS) found the risk of breast cancer associated with MHT use to be lower among women whose menopausal age was greater than 5 years when they initiated MHT [149–151]. This so-called gap theory may have a biological basis and suggests that a longer lag time between onset of menopause and initiation of hormones may be protective against carcinogenic effects of estrogen on the breast tissue [152]. The current clinical utility of the “gap theory” however is minimal given that symptom burden, and hence benefit from the use of MHT is the highest within the first few years of menopause.
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