Recently, two major epidemiological studies found that hormone replacement therapy (HRT) in postmenopausal women increased the risk of breast cancer. One of the studies also found that HRT increased the risk of cardiovascular disease and thrombosis. As a consequence, women were advised to cease this therapy.
However, detailed analysis of these studies suggests that the conclusions may be erroneous. Other studies suggest that the timing of initiation of HRT for healthy women is critical to achieving a beneficial outcome.
When begun within 5 years of menopause in healthy women, oestrogen-based HRT results in far greater benefits than adverse outcomes.
There is substantial objective evidence that the benefits of HRT include:
Reduced distressing symptoms of menopause.
Reduced risk of osteoporotic fractures, dementia and colorectal cancer.
Improved wellbeing, quality of life; improved vaginal epithelium, sexual enjoyment and bladder capacity.
Improved cardiovascular system, with reduced myocardial ischaemia and cardiovascular-related death.
The adverse effects of HRT include:
For over 70 years, women have used oestrogen-based hormone replacement therapy (HRT) to relieve distressing symptoms associated with menopause.1,2 In that period, a number of cohort and case–control studies demonstrated that HRT was associated with a reduction in cardiovascular disease,3,4 osteoporosis5,6 and dementia;7,8 other studies reported improvements in general wellbeing and sexual enjoyment.2,9
Doubt over the long-term safety of HRT led to the Women’s Health Initiative (WHI), a large, prospective, double-blind, placebo-controlled trial that used equine oestrogen (Premarin, Wyeth) and medroxyprogesterone acetate (Provera, Pfizer). The WHI was initiated under the auspices of the National Institutes of Health in the United States, and the results were published in 2002.10 Following wide media reporting and publicity, this study had a dramatic negative effect on the prescribing habits and recommendations for health professionals. Subsequently, a number of supplementary reports were published that provided detailed information on individual health issues,11-14 and which have resulted in diverging opinions regarding certain aspects of the WHI study.
Another study conducted by the WHI Investigators examined the effect of equine oestrogen alone on the health of postmenopausal women who had undergone hysterectomy, and was published in 2004.15
In the United Kingdom, a large cohort study, the Million Women Study (MWS) was published in 2003.16 It also received wide media exposure because it found that HRT increased the risk of breast cancer in trial participants.
The initial WHI study and the MWS found that oestrogen-based HRT increased women’s risk of breast cancer; the WHI study also reported that HRT increased the risk of myocardial infarction, stroke and dementia.10,11,16 Because of these negative findings, many health professionals stopped prescribing oestrogen-based hormonal therapy, and women were bewildered by the conflicting information regarding the safety of HRT.17
The initial WHI study recruited 16 608 postmenopausal women (exclusion criteria were hot flushes and a history of cancer), who received either Premarin plus Provera or a placebo. Although the study was intended to last for 8.5 years, it was terminated early (at 5.2 years) because of a non-significant increase in the incidence of breast cancer (38/10 000/year in the trial group v 30/10 000/year in the placebo group) and a statistically significant increase in myocardial infarction (37 v 30/10 000/year), thromboembolism (34 v 16/10 000/year) and stroke (29 v 21/10 000/year). There was also a statistically significant reduction in hip fractures (10 v 15/10 000/year) and in colorectal cancer (10 v 16/10 000/year).
A criticism of the WHI study is that two-thirds of the participants were over 60 years of age at recruitment (an average age of 63.3 years — 12–15 years after menopause); 34% were obese and a further 35% were overweight; 50% were past or current smokers; 35.7% were being treated for hypertension; 12.5% had elevated cholesterol levels; and 4.4% had diabetes. These older women are not typical of women seeking hormonal therapy as they enter menopause.18 During the trial, 42% of women on HRT had their treatment disclosed because of symptoms, increasing the potential for bias in the statistical review; and 10.7% of women on placebo initiated their own form of hormonal therapy,10 further complicating the trial’s conclusions.
These factors could have increased the risk of cardiovascular events in older women while using oral oestrogen, which passes directly to the liver and is known to increase the risk of thrombosis in women with damaged vascular endothelium.19 However, in spite of these problems, there was no increase in overall mortality among women taking HRT.10
In 2004, the WHI research group published another article of considerable significance.15 This study included 10 739 postmenopausal women with prior hysterectomy, who received either unopposed oral Premarin only or a placebo. After 6.8 years, it was found that women receiving oestrogen (without a progestogen) had a 23% reduction in the incidence of breast cancer (26 v 33/10 000/year), a reduction in myocardial infarction (49 v 54/10 000/year), and a 30% reduction in osteoporosis-related fractures (139 v 195/10 000/year). The risk of thrombosis (28 v 21/10 000/year) and stroke (44 v 32/10 000/year) remained.15
Later analysis of the original WHI data (Premarin plus Provera) showed that women who began hormonal therapy within the first 10 years after menopause had a reduced risk of myocardial infarction and no increased risk of breast cancer,12 suggesting that the timing of HRT initiation played a significant role in mediating the disease process.
Following closure of the WHI trial in 2002, women aged 50–59 years were invited to participate in an ancillary study involving arterial integrity as measured by calcification of the coronary arteries.14 After 7.4 years, women who continued taking oestrogen had markedly reduced calcification scores compared with women taking a placebo (83.1 v 123.1; P = 0.02), indicating that oestrogen begun early and continued for at least 8 years had a markedly beneficial effect on coronary vessels.14
From 1996 to 2001, all women due to have a routine mammogram in the UK were invited to enter a study to determine factors that may increase the risk of breast cancer. The results suggested that women who were taking some form of hormone therapy had an increased risk of breast cancer, whereas women who had ceased HRT 12 or more months previously had no increased risk.16 Although this large cohort study supported the concept that HRT led to breast cancer, the study came under intense criticism from other epidemiologists and clinicians, because data collection and interpretation were considered to be misguided.20,21
Major criticisms were: just over 50% of invited women eventually had a mammogram, suggesting there could have been self-selection bias in the study population; the number of women in the UK using HRT were over-represented in the study (32% v 19%); the average time from beginning therapy to diagnosis of cancer was brief (1.2 years), suggesting to clinicians that, in many cases, cancer had been present before initiating treatment and that hormones had accelerated its growth, rather than causing it; the study’s failure to take into account that a sizeable number of women switched treatments during the follow-up period — some ceased therapy (22%), others resumed their HRT (19%) and 11% appeared to initiate HRT during the study period.22
The number of women diagnosed with breast cancer in the US fell by between 6% and 8% from 2000 to 2004.23,24 It has been suggested that the fall was due to a 40% reduction in the use of HRT following publication of the WHI studies and the MWS,25-31 and it was claimed that this was further proof that hormones increased the risk of breast cancer.
Clinical experience,32-36 however, suggests that the mutations that result in breast cancer37,38 begin to accumulate during the premenopausal years39-43 and having developed in a cell, persist in that cell until mutations in immunoglobulins, and other adhesion proteins allow invasive cancer to occur, sometimes many years later. Hormones promote rapid growth of a pre-existing breast disease. If hormones were responsible for promoting breast cancer, the first evidence of a reduction in breast cancer incidence would not be detected for at least 1–2 years after women had ceased hormone therapy. However, the reduction in breast cancer incidence in the US was observed before, or coinciding with, the publication of the WHI reports in 2002.23,24 In Europe, there was also a sharp reduction in the use of HRT, but no accompanying fall in the detection of breast cancer.44 More recently, Chlebowski and colleagues reported the results of a review of the incidence of breast cancer 3 years after the WHI study was completed.45 Within 2 years of ceasing Premarin and Provera the increased incidence of breast cancer, evident in the initial WHI study, had reverted to that in the placebo group and it was suggested that this confirms that HRT was responsible for the increase in detected breast cancer. The results unfortunately do not clarify whether HRT caused or promoted breast cancer. The short interval between stopping HRT and an alteration in the number of cancers being reported suggests that hormones were promoters, not initiators, of breast cancer. A likely explanation is that the increase detected 2 years after starting HRT was due to accelerated growth of cancer in-situ and microinvasive cancers. Ceasing HRT would remove the stimulus for growth of these pre-existing cancers and result in a temporary reduction in the detection of tumours.46 Another possible cause for the drop in diagnosed cancers is the reported reduction in the use of screening mammography over the years from 1998.30,31
Box 2 summarises the findings of the WHI studies and the MWS.
According to the Australian Bureau of Statistics (ABS), breast cancer accounted for 4% of female deaths in Australia in 2006,47 and clinical reports from the Australian Institute of Health and Welfare confirm that almost 25% of breast cancers occur in women under the age of 54 years.48 Evidence that the changes resulting in breast cancer begin in young women has been confirmed by reports from a number of post-mortem studies on women who have died from non-malignant causes.39-43 These autopsy studies found that at least 20%–30% of premenopausal women, including some adolescents, have already developed a large reservoir of duct cell hyperplasia or cancer in situ. In a study of breast tissue retrieved during medicolegal autopsies, researchers found that cancer in situ was present in 37% of women aged 40–54 years, and undiagnosed invasive cancer was present in 2%.43
At least 90 aberrant genetic mutations are implicated in breast cancer.37,38 It is now accepted that most mutations are either inherited or occur spontaneously during mitosis.32 Based on epidemiological studies, there are claims that HRT is a mutagen that leads to breast cancer. A complex hypothesis has been proposed, which states that oestradiol is converted by specific enzymes into catechol oestradiol, which, through further biochemical metabolism to quinone intermediates, is asserted to be a weak mutagen.49 Synthetic progestogens have also been blamed, based on epidemiological evidence reporting an increased incidence of detected invasive breast cancers when combined oestrogen and progestogens have been used,26 but there is no biological evidence to support either oestradiol or progestogens as a mutagen that leads to breast cancer.
Large cohort studies, observing the outcomes of women who have had diagnostic breast biopsies performed, confirm that, over periods ranging from 8–17 years, cancer developed twice as frequently in women with simple duct hyperplasia and about six times more often among women with atypical hyperplasia;33-35 over the same period, invasive cancer occurred in 10%–15% of women with a history of cancer in situ.33-36 These studies confirm that cell changes proceed from hyperplasia and atypical hyperplasia through cancer in situ to invasive cancer as cells accumulate genetic mutations, and that these mutations begin years before invasive cancer is diagnosed. Following menopause, HRT accelerates the growth of an already existent lesion. Ceasing HRT removes the accelerant, thereby reducing the number of cases likely to be diagnosed during a particular period. Appreciating the time sequence and the biological and clinical events underlying the development of cancer32,37 helps us understand the apparent conflicts that currently exist between epidemiologists and clinicians regarding hormones and breast cancer.
According to the ABS, in 2006, 17% of registered female deaths were attributable to ischaemic heart disease and 8.6% to stroke.47 Women have a major cardiovascular advantage over men of the same age until about 10 years after menopause, when the risk of cardiovascular disease begins to equal that of men.1 This protection for women up to the age of 60 years is thought to be due to the residual beneficial effect of premenopausal oestrogen on the arterial and cardiac endothelium and musculature.13,14
Although the WHI study suggested an adverse effect of HRT on the cardiovascular system, it is likely that the time at which hormone therapy is initiated plays a significant role in the development of cardiovascular disease. A study in macaque monkeys found that if oestrogen therapy is delayed for more than 2 years, its protective effect is lost.50 Extrapolating these results to humans suggests that HRT should be initiated within 6 years of menopause (the “window of opportunity”).50 Clinical studies in humans support these animal study results.15,51,52 When HRT is initiated within a few years of menopause, women continue to experience a 40%–60% reduced risk of myocardial ischaemia and hypertension,12,13,53-55 but 2–3 times increased risk of thromboembolism, to 8 / 10 000/year.10,15,19
According to the ABS, dementia was responsible for about 5% of postmenopausal mortality in Australia in 2006.47
US researchers examined the effect of HRT on cognitive functioning and the incidence of dementia in 7479 women from the WHI study group.11 The women were all aged over 65 years when they entered the study, and were followed up for 4–5 years.11 The results from this research indicated that HRT provided no advantage in protection from dementia, and may have increased the number of women who developed dementia.11 As a result, it was recommended that hormonal therapy should not be used to prevent or treat dementia in women.
However, to prevent or reduce the impact of a disease, it is important to begin prophylactic therapy before the onset of the disease — certainly before the age of 65 years. Research has demonstrated that β-amyloid deposition is reduced in castrated animals fed an oestrogenic therapy regimen,56 and clinical studies have shown that women who begin oestrogen therapy at or soon after menopause have a reduced risk of dementia.57
Oestrogen suppresses osteoclastic activity, stimulates osteoblasts, and maintains the essential coupling between bone formation and bone resorption. Women who begin and continue HRT have a much reduced risk of osteoporotic fractures.10,17 Studies have consistently demonstrated that women who begin HRT within the window of opportunity have a 30%–50% reduction in the risk of fracture of spine or hip.5,10,17
Because of the fear of adverse events, a number of authorities have recommended that HRT be used for the shortest possible period.58,59 However, a 22-year study of 8801 women showed that those using HRT from menopause, and continuing for the remainder of their lives, lived longer with fewer adverse events than women who did not use HRT.51 The reduction in the risk of death from all causes was 15%. Similar studies have confirmed that women who begin HRT at or within a few years of menopause have fewer cardiovascular events or breast cancers, and live longer than similar women who never use HRT.42,60
HRT was introduced in the early 1930s to relieve hot flushes, sweats, insomnia, dry vagina and to improve the quality of life for menopausal women. Over the past 70 years, it has continued to be the most effective therapy to reduce these symptoms. Recent studies also confirm that HRT is still the therapy of choice to maintain health, wellbeing and sexual enjoyment;61 negative reports of increased adverse events must be balanced against the benefits of starting HRT early and continuing therapy.
abating menopausal symptoms;
improving quality of life;
maintaining the cardiovascular system;
reducing osteoporosis-related fractures;
reducing the risk of dementia; and
Adverse effects include an increase in thrombosis and stroke when HRT is administered orally to women who have an underlying cardiovascular disease, and HRT makes pre-existing breast cancer grow more rapidly.
1 Risk of medical events in the WHI studies
may accelerate pre-existing breast cancer growth
increases the risk of thrombosis and stroke
may increase the risk of myocardial ischaemia
reduces the risk of fractures.
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