Review articleBack to the future: Hormone replacement therapy as part of a 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.
References (86)
Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence
Prev. Med.
(1991)A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study
BJOG
(2002)Too much of a good thing? Use of progestogens in the menopause: an international consensus statement
Fertil. Steril.
(1989)Coronary heart disease and menopause management: the swinging pendulum of HRT
Atherosclerosis
(2009)Conventional-dose hormone therapy (HT) and tibolone, but not low-dose HT and raloxifene, increase markers of activated coagulation
Maturitas
(2006)17β-Oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells
Biochim. Biophys. Acta
(1998)- et al.
Role of annexin II in estrogen-induced macrophage matrix metalloproteinase-9 activity: the modulating effect of statins
Atherosclerosis
(2006) The risk of fatal stroke in Finnish postmenopausal hormone therapy users before and after the Women's Health Initiative: a cohort study
Maturitas
(2015)The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women
Prog. Cardiol. Dis.
(1995)Estrogen for women at varying risk of coronary disease
Maturitas
(1998)
A window of opportunity: the reduction of coronary heart disease and total mortality with menopausal therapies is age and time dependent
Brain Res.
Effect of hormone replacement therapy on age-related increase in carotid artery intima-media thickness in postmenopausal women
Atherosclerosis
Long-term hormone replacement therapy delays the age related progression of carotid intima-media thickness in healthy postmenopausal women
Maturitas
Hormone replacement therapy in perimenopausal women and 2-year change of carotid intima-media thickness
Maturitas
Impact of gender in primary prevention of coronary heart disease with stain therapy: a meta-analysis
Int. J. Cardiol.
Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials
J. Am. Coll. Cardiol.
Two to three years of hormone replacement treatment in healthy women have long term preventive effects on bone mass and osteoporotic fractures:the PERF Study
Bone
Conjugated equine estrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomized placebo-controlled trial
Lancet Oncol.
Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for 7:e3411 management of menopausal hot flashes and postmenopausal bone loss
Steroids
Postmenopausal hormone therapy and mortality
N. Engl. J. Med.
Estrogen therapy in postmenopausal women: effects on cognitive function and dementia
JAMA
Decreased mortality in users of estrogen replacement therapy
Arch. Intern Med.
Hormone therapy to prevent disease and prolong life in postmenopausal women
Ann. Intern Med.
Guidelines for counseling postmenopausal women about preventive hormone therapy
Ann. Intern. Med.
Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women
JAMA
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial
JAMA
Prevention of diseases after menopause
Climacteric
NHLBI stops trial of estrogen plus progestin due to increased breast cancer risk and lack of overall benefit
South Med. J.
Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials
JAMA
Increased cardiovascular mortality risk in women discontinuing postmenopausal hormone therapy
J. Clin. Endocrinol. Metab.
Trend in incidence of osteoporosis-related fractures among 40 to 69 year old women: analysis of a large insurance claims database, 2000-2005
Menopause
Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization
Menopause
The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women age 50 to 59
Am. J. Public Health
The decrease in incidence of breast cancer in the United States
Oestradiol NEJM
Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies. Part 5. Secular trends
J. Fam. Plan. Reprod. Health Care
Molecular and cellular basis of cardiovascular gender differences
Science
Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system
Cardiovasc Res.
27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen
Nat. Med.
Even as mortality fell in most US counties, female mortality nonetheless rose in 42.8 percent of counties from 1992 to 2006
Health Aff. (Millwood)
The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women, Part 1: comparison of therapeutic efficacy
J. Am. Geriatr. Soc.
Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality
Menopause
Coronary heart disease mortality and hormone therapy before and after the Women's Health Initiative
Obstet. Gynecol.
Vaginal estradiol use and the risk for cardiovascular mortality
Hum. Reprod.
Cited by (102)
Sex differences in antioxidant defence and the regulation of redox homeostasis in physiology and pathology
2023, Mechanisms of Ageing and DevelopmentManagement of menopause: a view towards prevention
2022, The Lancet Diabetes and EndocrinologyThe Canadian Women's Heart Health Alliance Atlas on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women — Chapter 4: Sex- and Gender-Unique Disparities: CVD Across the Lifespan of a Woman
2022, CJC OpenCitation Excerpt :Of additional importance are the MHT characteristics including hormonal formulation, dose, route of estrogen administration (eg, transdermal, oral, vaginal), whether with or without progesterone (unopposed vs combined estrogen and progesterone), and mode of delivery (cyclical or continuous).56,57,60 Evidence for CV effects of MHT has accrued and evolved over the past several decades.60,72 Large observational studies and meta-analyses published in the 1980s suggested MHT prevented CVD and lowered all-cause mortality.
Mesenchymal stem cells prevent ovariectomy-induced osteoporosis formation in mice through intraosseous vascular remodeling
2021, Biochemical and Biophysical Research CommunicationsReal-world practice of estrogen and progestogen prescriptions in menopausal women in Japan: A descriptive study using a Japanese claims database
2023, Journal of Obstetrics and Gynaecology Research