Elsevier

Atherosclerosis

Volume 254, November 2016, Pages 282-290
Atherosclerosis

Review article
Back to the future: Hormone replacement therapy as part of a prevention strategy for women at the onset of menopause

https://doi.org/10.1016/j.atherosclerosis.2016.10.005Get rights and content

Highlights

  • Randomized trials taught us that age at initiation of HRT is critical.

  • In healthy younger women (<10 years from menopause or < 60 years old), estrogen and certain types of HRT reduce coronary disease, osteoporosis, and all-cause mortality.

  • HRT should be considered as part of a prevention strategy in younger women, initiated at the onset of menopause.

  • The type of HRT and its duration of use require more study.

Abstract

In the late 1980s, several observational studies and meta-analyses suggested that hormone replacement therapy (HRT) was beneficial for prevention of osteoporosis, coronary heart disease, dementia and decreased all-cause mortality. In 1992, the American College of Physicians recommended HRT for prevention of coronary disease. In the late 1990s and early 2000s, several randomized trials in older women suggested coronary harm and that the risks, including breast cancer, outweighed any benefit. HRT stopped being prescribed at that time, even for women who had severe symptoms of menopause. Subsequently, reanalyzes of the randomized trial data, using age stratification, as well as newer studies, and meta-analyses have been consistent in showing that younger women, 50–59 years or within 10 years of menopause, have decreased coronary disease and all-cause mortality; and did not have the perceived risks including breast cancer. These newer findings are consistent with the older observational data. It has also been reported that many women who abruptly stopped HRT had more risks, including more osteoporotic fractures. The current data confirm a “timing” hypothesis for benefits and risks of HRT, showing that younger have many benefits and few risks, particularly if therapy is predominantly focused on the estrogen component. We discuss these findings and put into perspective the potential risks of treatment, and suggest that we may have come full circle regarding the use of HRT. In so doing we propose that HRT should be considered as part of a general prevention strategy for women at the onset of menopause.

Introduction

In the late 1980s, several observational studies and meta-analyses suggested that hormone replacement therapy (HRT) for women after menopause was beneficial for prevention of osteoporosis, coronary heart disease (CHD), and dementia and decreased all-cause mortality [1], [2], [3], [4], [5]. Indeed it was a recommendation of the American College of Physicians to advocate the use of HRT as a prevention strategy in 1992 [6]. In the late 1990s and early 2000s, several randomized trials in mostly older women in which HRT was initiated 10 or more years after menopause suggested coronary harm and risks outweighed benefit [7], [8], [9]. Almost immediately after the initial publication of data from the hormone trial of the Women's Health Initiative (WHI) [9], HRT stopped being prescribed, even for women who had severe symptoms of menopause. Subsequently, reanalyzes of the older randomized trial data, using age stratification, as well as newer studies and meta-analyses have been consistent in showing that when initiated in younger women, 50–59 years or within 10 years of menopause onset, HRT decreases CHD and all-cause mortality; and did not have the perceived risks including breast cancer. These newer findings in younger women with initiation of HRT within 10 years of menopause are consistent with the older observational studies of younger women who initiated HRT at the time of menopause.

In public health, prevention strategies have been instituted with the expectation that it would be beneficial over time and reduce human suffering and mortality. Most aging-related diseases in women occur on average about 10 years after the onset of menopause [10]. Thus, an important opportunity is afforded by potentially intervening with preventative strategies at the onset of menopause. The coronary benefit in younger women using HRT, the reduced all-cause mortality and other benefits in terms of reduction in menopausal symptoms, osteoporosis prevention, prevention of new onset diabetes mellitus and improved quality of life; as well as the demonstration of cost effectiveness and the lack of effectiveness of other prevention strategies for younger healthy women make a compelling argument for the use of HRT for prevention. We propose here that use of HRT, and specifically the use of estrogen, should be part of a strategy for prevention of chronic diseases after menopause, and not restricted only for the treatment of moderate to severe hot flushes.

Section snippets

What was known about estrogen in women after menopause?

As introduced above, many observational studies showed a benefit of HRT for several endpoints. A meta-analysis and pooled analysis showing a coronary benefit of 0.65 (0.59–0.72) and a projected increase in longevity among users [5] led the American College of Physicians to publish guidelines in 1992 [6]. This statement suggested that “all women, regardless of race, should consider preventive hormone therapy” and that “women who have coronary heart disease or who are at increased risk for CHD

Randomized trials of HRT

Despite strong observational data, it was deemed important to carry out randomized trials to assess the purported coronary benefits of HRT in postmenopausal women. In the 1990's several secondary prevention trials were begun [7], [8], [9]. Just as WHI was beginning, reports from these trials, studying the effects of estrogen/progestogen versus placebo in women with established CHD showed no overall benefit with a complex pattern of “early harm” (more coronary events within first year of

Aftermath of WHI: fractures, CV events, mortality

The large fall in use of HRT has had profound clinical consequences for postmenopausal women whose health and well-being has suffered. The reluctance of health care professionals to prescribe HRT has denied many women adequate and effective relief from menopausal symptoms and has impaired their quality of life. In addition, there are data showing that stopping HRT may result in increased CHD, stroke and all-cause mortality [15]. Of equal and well-documented concern is the substantial increase

Why the initial reports from WHI and the other secondary prevention trials were different from the observational data

Although the beneficial effects found in the earlier observational studies was hypothesized to be due to inherent biases of observational data such as a “healthy user effect”, adjustments to the data have not negated these findings. A major difference between observational studies and randomized clinical trials of HRT is the age at initiation of therapy; observational studies included women who chose to start HRT around the time of menopause mainly for symptomatic relief, whereas the average

Coronary heart disease and all-cause mortality

Mortality rates in women have risen in 44% of U.S. counties since 2002 along with the concomitant reduction in use of HRT, in contrast, mortality rates have risen in only 3% of counties for men [27]. While it is unclear if this increase in mortality has anything to do with HRT, over the last decade, data have accumulated to indicate the relative effectiveness of HT as a prevention strategy for CHD in postmenopausal women [28]. At the same time, no other primary prevention strategy, other than

Carotid artery intima-media thickness

Carotid artery intima-media thickness (CIMT) is a direct measurement of subclinical atherosclerosis that is predictive of future clinical cardiovascular events, CHD and stroke. Observational and case-control studies show that HRT was associated with a lower average level of CIMT compared to non-users [45], [46], [47]. In a randomized controlled trial of HRT in perimenopausal women, 2-year change in CIMT was reduced relative to placebo; however the confidence intervals were wide, indicating no

Coronary artery calcium

Even though coronary artery calcium is a late manifestation of atherosclerosis, some [54], [55] but not all [56] observational studies suggest that long-term HRT is associated with less accumulation of coronary artery calcium. Coronary artery calcium is correlated with atheromatous plaque burden and future risk of clinical CHD events. In an ancillary substudy of younger women (<60 years) in the WHI CEE trial, after an average of 7 years of treatment, women who had been randomized to CEE had

Sex specificity of preventive therapies

Sex-specific meta-analyses that have carefully separated primary and secondary prevention trials and only included women in the analyses do not show a statistically significant reduction of CHD in primary prevention with lipid-lowering, including statin therapy in women [58], [59], [60]. Under both primary and secondary prevention, lipid-lowering therapy has a null effect on all-cause mortality in women [58], [59], [60]. A sex-specific effect is similarly seen for aspirin where primary

Use of HRT in women at the onset of menopause

For young healthy women at the onset of menopause, the choice of prescribing some form of HRT is straight forward if she is symptomatic. This includes more than “hot flushes”, and may involve body aches and pains, genitourinary symptoms, sleep disturbances, and depressive mood as well as other less precise symptoms which affect the quality of life after menopause. It has been established that use of HRT in women at the onset of menopause is cost-effective [67]. The median persistence of

What are the real risks of HRT in young healthy women?

If HT is to be considered more broadly for postmenopausal women, it is important to examine the real risks of such exposure. As noted above, the reported risks associated with HRT in the WHI trials were not statistically significant, with the exception of venous thrombosis and ischemic stroke in older women. In women <60 years of age and/or <10 years-since-menopause the only statistically significant risk with HRT in WHI was a rare risk of deep vein thrombosis (Fig. 1). Breast cancer risk with

The choice of the HRT regimen may be critical

While there are no randomized trial data to guide specific prescriptions for HT, particularly with a goal of prevention, there are some general principals which may be employed. It is clear however that woman react differently in terms of treatment of symptoms and side effects, and flexible prescribing should always be considered. In general HT should be estrogen-based. That is, progestogen use should be minimized merely for endometrial protection in women with a uterus, and not used in

Conclusions

In the future, we are likely to have more data available, particularly in the area of personalized medicine, and pharmacogenomics. Thus a more personalized approach will be available to guide therapy, as well as the type of therapy and the particular regimen when choosing to use HRT.

Until then we can only rely on good clinical judgment and what data we have at hand. Based on the discussion above we put forth the notion that prevention of diseases after menopause should remain the primary focus

Conflict of interest

Dr. Lobo has consulted for Pfizer, Teva and Allergan and conducts clinical trial work for TherapeuticsMD. Dr. Pickar was formerly an employee of Wyeth Research, and has received consultant fees from Wyeth/Pfizer, Besins Healthcare, Shionogi Inc, Metagenics, Radius Health and TherpeuticsMD, and has stock options with TherapeuticsMD. Dr Stevenson has received grants/research support and/or speakers fees from Abbott, Mylan and Pfizer; consulting fees from Abbott and Pfizer; and speaker's honoraria

Author contributions

All authors contributed significantly to the analysis, composition and writing of this manuscript.

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