Hormone replacement therapy: a 2008 perspective

Article Outline

• Abstract
• Introduction
• Cardiovascular disease
• Breast cancer
• Ovarian cancer
• Thromboembolism
• Fractures
• Cognitive function and dementia
• Stroke
• Bowel and uterine cancers
  • Revised risk/benefit ratios for HRT
• Menopausal symptom control and quality of life
• Tibolone
• Early side effects
• Conclusion
• Competing interests
• Further reading
• Copyright

Abstract 

New clinical data and recent re-analyses of data from the Women’s Health Initiative (WHI) have greatly changed the perception of hormone replacement therapies (HRTs) since the media excitedly reported the first findings of the combined HRT arm of WHI in 2002. The initial adverse finding of an overall early increase in cardiovascular risk in both WHI and the Women’s International Study of long Duration Oestrogen after Menopause in women who start or recommence HRT on average 13–14 years after menopause has been overshadowed by recent evidence supporting a cardioprotective effect of HRT when it is commenced near menopause. Most HRT is commenced in this early ‘therapeutic window’ when coronary calcification and atherosclerosis appear to be inhibited by oestrogen. Some neuroprotective effects are also hypothesised when HRT is commenced at this time. The effect of HRT on stroke when prescribed near menopause is not clear as it is uncommon at this age.

A doubling in the risk of thromboembolism is still the main risk of HRT. The absolute risk is small near menopause when thromboembolic risk factors are not present and may be much less with non-oral routes. Breast cancer is a fear for many users but WHI showed a reduction of eight breast cancers per annum per 10,000 women years in oestrogen-only users at 7 years and no significant increase in first-time users of combined HRT until after 7 years when it was 8/10,000 per annum or less than 0.1%.

Weight gain in users of HRT and placebo is similar around menopause.

The main indications for HRT remain the control of menopausal symptoms where quality of life is gained and for the prevention of osteoporotic fractures, particularly in younger menopausal women where the risks are low. Other benefits include a reduction in diabetes and death.

HRT must be individualised and tailored to minimise the start-up symptoms of bleeding on combined continuous regimens and breast tenderness when oestrogen levels are too high. Menopausal therapies are moving towards safer regimens, which minimise or eliminate systemic progestogen, safer routes (non-oral), safer lower doses and safer women.

Keywords: hormone replacement therapy, menopause, oestrogen, progestogen, risks and benefits

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Introduction 

Prior to 2002, and using the Australian National Health & Medical Research Council levels of evidence, Level 2 observational studies – which were mostly of women who commenced hormone replacement therapies (HRTs) near menopause for symptom control – suggested that long-term therapy conveyed cardiovascular and fracture benefit but increased risk of breast cancer and thromboembolism. Initial results of the Level 1 long-term randomised controlled trial (RCT) of HRT – Women’s Health Initiative (WHI) – showed that after 5 years of combined oestrogen and progestogen therapy, in a relatively asymptomatic, elderly population commencing therapy on average about 13 years after menopause, there was a significant reduction in fractures but no overall cardiovascular benefit in this population and an increase in breast cancer and thromboembolism.

The media reaction to this first view of the WHI data encouraged up to two-thirds of HRT users to stop therapy, often without medical consultation. Various advisory bodies issued strongly worded guidance, based on the first paper, to the effect that HRT should be used at the lowest dose for the shortest possible time and only in severely symptomatic women. Recent analyses from WHI, other RCTs and observational and animal studies have now unified much of the HRT data and changed the risk:benefit ratio for the large majority of women who commence HRT for symptom control around menopause. It is mostly good news (see Figure 1).

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• Figure 1. 

  Graphic summary of the main increased and decreased morbidities per annum reported in the Women’s Health Initiative (WHI) for the combined HRT a and oestrogen-only arms b compared with placebo per 10,000 women years in women aged 50 to 79 at trial entry (mean age 63). Data for women under the age of 60 years in the WHI have now been published for many outcomes in a variety of publications and have been combined for both regimens in c and d. WHI was not powered for such sub-analyses and significance levels are not shown.

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Cardiovascular disease 

There are now strong data in support of the ‘critical therapeutic window’ hypotheses that oestrogen is cardioprotective if initiated around menopause when there are still vascular oestrogen receptors responsive to exogenous HRT. HRT administered around menopause appears to reduce the progression of atherosclerotic plaque but if HRT is administered many years after menopause, it is not beneficial and may sometimes disrupt established plaque with adverse effects.

A meta-analysis of RCTs (Level 1 evidence) shows a statistically and clinically significant 39% reduction in cardiac events compared with placebo control groups when HRT is initiated under the age of 60 years (odds ratio (OR) 0.68; 95% confidence interval (CI) 0.48–0.96); however, this cardioprotective effect was not seen in older women initiating HRT after the age of 60 years (OR 1.03; 95% CI 0.91–1.16). When HRT is initiated many years after menopause there is an increase in cardiac events during the first year of therapy (HR 1.47; 95% CI 1.12–1.92). Subsequent cardiac morbidity is reduced after 2 years of HRT in these older women (HR 0.79; 95% CI 0.67–0.93). All-cause mortality in younger HRT users compared with placebo is also significantly reduced (HR 0.61; 95% CI 0.39–0.95). Currently data from Level 1 trials near menopause suggest that oestrogen-only regimens may offer greater cardioprotection than some combined regimens but more research is needed on the timing and type of progestogen therapy.

The two long-term Level 1 trials of HRT (WHI and Women’s International Study of long Duration Oestrogen after Menopause (WISDOM)) enrolled women on average 13–14 years post-menopause because the outcomes being measured were more prevalent in later age. The populations in these trials were unrepresentative of symptomatic women who initiate HRT near menopause. Although WHI alone was not powered for sub-analyses of cardiac events, in the 8832 women under the age of 60 years in the two HRT trial arms, the combined RCT data now indicate cardioprotection in women initiating HRT near menopause, especially when oestrogen-only regimens are used. A recent paper from the WHI investigators reported on coronary artery calcification, which reflects calcified atheroma and total plaque burden, in the oestrogen-only arm of WHI, 8.7 years after randomisation. In those who were 80% or more compliant, there was 61% less atherosclerotic plaques in women whose mean age was 55 years at baseline, as compared with the placebo group (p = 0.004).

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Breast cancer 

Prior to WHI, observational studies (Level 2) had suggested an increased relative risk of breast cancer with long-term combined HRT (cHRT) of 1.53 after a median of 8 years. WHI actually reported half this risk with a relative risk after 5.6 years of cHRT of 1.26 (adjusted 95% CI 0.83–1.92). However, the media often highlighted the relative risk without explaining the absolute risk. The absolute increased risk in WHI was 8 per 10,000 women years, or less than 0.1% per annum. Systematic reviews of all the Level 1 data now suggest an increased risk of breast cancer on cHRT of 4 per 10,000 women years or 2 per 1000 women after 5 years. Some groups have preferred to use worst scenario statistics that are derived from observational data including the Million Women’s Study (Level 3-3). Observational data may inflate the real risk (due to selection and detection biases etc.) and intention to treat analyses of RCTs may reduce the real risk due to non-compliance with therapy. Both methodologies have their merits and demerits! Another way to counsel about risk is to compare the increased relative risk seen in WHI for breast cancer, which was 1.26 (1.00–1.59) to other common risk factors. Thus, this relative risk is similar to a late menopause at age 55 years or more (RR 1.22), three alcoholic drinks per day (RR 1.4) or nulliparity (RR 1.67). Later analysis of the WHI data showed that there was no significant increase in breast cancer among those who initiated cHRT for the first time during the 7 years of WHI.

Even better news from WHI came when the oestrogen-only arm showed a non-significant reduction in breast cancer by 7.1 years in this hysterectomised group, a group in whom many would have expected to observe an increase in risk of breast cancer. These results challenge many of the beliefs about oestrogen and breast cancer but may incriminate systemic progestogen. Data on regimens, which may avoid the undoubted risk of long-term cHRT, e.g. tibolone or intrauterine progestogen and systemic oestrogen, are awaited. Observational data (Level 2) has suggested that more than 20 years of oestrogen-only therapy may increase breast cancer rates.

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Ovarian cancer 

Data from the Women’s Health Study, observational studies and recently the Million Women’s Study show a non-significant increase in ovarian cancer after 5 years of cHRT but a significant increase after 5 years of unopposed oestrogen-only therapy. The increased absolute risk in the Million Women’s Study was estimated as one in 2500. This risk is mostly seen in women who have had a hysterectomy with ovarian conservation and take oestrogen for more than 5 years. This group is about 8% of HRT users. In this group, the reduction in breast cancer seen in WHI would balance the mortality associated with both cancers. Tibolone use was not associated with a rise in ovarian cancer.

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Thromboembolism 

This remains the main short-term serious risk of HRT. The risk of thromboembolism on oral HRT appears to be greatest in the first year or two of use and is highest in those with thrombophilia and/or obesity. The absolute risk varies with individual risk for thromboembolism. Risk varies with age at initiation and overall the increased risk is about one in 10,000 at the age of 50 years. In the future, general screening for thrombophilia may become a cost-effective proposition. Currently, clinical risk factors may merit screening. Non-oral routes of oestrogen, adding micronised progesterone or pregnane-derived progestogens when a uterus is present, have not been associated with thromboembolic risk (Level 2 evidence). However, these have not been studied in Level 1 long-term randomised trials.

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Fractures 

The expected one-third reduction of fractures (hip, spine and overall) seen in observational studies was confirmed by WHI (RR 0.66). Importantly, this reduction was seen in a population not screened for osteoporosis. HRT remains a cost-efficient and relatively safe option for the prevention of fractures when initiated before the age of 60 years in osteoporotic women who are often also symptomatic. Such women may have few other cost-efficient therapeutic options and this indication for HRT needs to be revisited in light of the recalculated risks of HRT (especially low-dose oestrogen-only regimens).

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Cognitive function and dementia 

The effect of HRT on the brain is likely to remain controversial because a very long-term trial from menopause will probably be impossible. Observational studies (Level 2) support the ‘critical window hypothesis’ where HRT use from near menopause shows more cognitive benefit than commencing HRT many years after menopause. WHI studied only women commencing HRT over the age of 65 years and, like its cardiovascular data, suggested slight detriment in this older group. The Cache County observational study noted a 59% reduction in dementia in early menopausal users who took therapy for more than 10 years. Other Level 2 studies, which have not distinguished between early or late initiation of HRT, have not seen consistent cognitive benefit.

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Stroke 

In WHI, no effect of cHRT on stroke was seen in the first year of therapy. The risk ratios increased to 1.72 over the next 4 years and decreased to 0.66 in Year 6. Yearly confidence intervals have not been published but, in the elderly WHI population, the overall absolute increased risk was eight per10,000 per annum (0.08%). The final hazard ratio (HR) for stroke was 1.31 (adjusted 95% CI 0.93–1.84). In the oestrogen-only arm of WHI, the HR was 1.39 (adjusted 95% CI 0.97–1.99). Again the prevalence of stroke is age-dependent and the numbers under the age of 60 years were small and too small to test the critical window hypotheses for stroke. An increased risk of transient ischaemic attacks and strokes must currently be presumed as likely in women initiating HRT many years after menopause.

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Bowel and uterine cancers 

In the cHRT arm of WHI, a small decrease in these cancers was seen of around eight per 10,000 per annum. Oestrogen – only therapy had no effect on bowel cancer in WHI.

Revised risk/benefit ratios for HRT 

Figure 1(a) and (b) show the overall main morbidities assessed initially in the overall WHI population who were on average 13–14 years post-menopause, an average age of 63–64 years and had a high prevalence of cardiovascular risk factors on entry to the trial. These mostly asymptomatic women were not representative of HRT users who usually start HRT near menopause. In contrast, recent data from WHI allows compilation of a very different morbidity profile for women in the combined arm and the oestrogen-only arm who commenced therapy under the age of 60 years (Figure 1(c) and (d)). Although WHI was underpowered to study women under the age of 60 years, the 8832 women in WHI under the age of 60 years are the largest number in a single randomised placebo-controlled trial.

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Menopausal symptom control and quality of life 

Symptom control and perceived improved quality of life are the main reason for the commencement of HRT and for high continuation rates. Systematic Level 1 reviews show that HRT very efficiently controls vasomotor symptoms and urogenital symptoms. In WHI, joint pains were significantly reduced by HRT and increased on cessation of therapy. Disease-specific quality of life scores improve in symptomatic women commencing HRT and are related to improvements in sleeplessness, tiredness and sexuality. The media scare in 2002 prompted medical review and cessation of long-term HRT in some users who had no further indication for its use. However, many more women inappropriately stopped therapy or never started HRT because of media and medical perception of the risks of HRT. Ironically many women who experienced menopause after 2002 may have missed a therapeutic window for cardioprotection and possible cognitive benefit and also suffered unnecessary menopausal symptoms if they avoided or their advisors denied them the option of HRT. Many women have reported that their doctor or their pharmacist has said that HRT was too dangerous and they should use non-evidence based complementary therapies.

No complementary therapy has a greater effect than the placebo effect seen in HRT trials. Some drugs acting on the brain – e.g. selective serotonin reuptake inhibitors – have a moderately better effect than placebo on reducing vasomotor symptoms. So called ‘bioidentical’ or ‘natural’ unregistered hormones individually compounded in untested doses and combinations and often titrated with unvalidated salivary hormone assays are mostly unassessed for efficacy or long-term safety.

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Tibolone 

Although not a traditional HRT, tibolone is a steroid with oestrogenic, progestogenic and androgenic properties and currently has a good safety profile in short-term Level 1 RCTs up to 4 years. It is an all-in-one single dose oral post-menopausal therapy with a moderately effective action on menopausal and urogenital symptoms, libido and bone. Tibolone does not stimulate breast cell proliferation or increase breast tissue density. Randomised controlled trials up to three years do not show any increase in breast cancer rates. However, tibolone is not recommended after breast cancer in women on adjuvant therapy because of potential reduction in the efficacy of these therapies. There is a question mark about a small increased risk of stroke seen in one trial of elderly women with osteoporosis but this result was confounded by unusually low numbers of stroke in the placebo group. Similarly the Million Women’s Study (Level 3-3) showed an association with breast cancer that may have been confounded by the selection of women with breast cancer for tibolone therapy.

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Early side effects 

In the Cochrane systematic review of Level 1 studies of HRT for vasomotor symptoms, the only two significantly increased side effects were breast tenderness and start-up bleeding on combined continuous HRT in women with a uterus. Breast tenderness may be transient in the first month or can usually be reversed with oestrogen dose reduction. Diminishing bleeding for several months is normal on continuous combined regimens especially if started near the menopause when a cyclical progestogen and continuous oestrogen may be a better initial option. The key to successful HRT and patient adherence is to tailor their therapy, e.g. as above and to consider non-oral routes when oral oestrogen absorption may be compromised by irritable bowel syndrome, malabsorption syndromes, increased liver metabolism, and drug interactions –e.g. H2 antagonists and complementary medicines such as St John’s Wort. Doses should be the lowest that are effective and length of therapy to avoid on-going symptoms is usually for years rather than months. One option is to try a period of time ‘off’ HRT every 4–5 years with an expectation that about half will note a loss of quality of life warranting possible recommencement of therapy. At this time the risk:benefit ratio for that woman using that regimen (often at half the previous dose) can be explained allowing an informed decision by the woman about further therapy.

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Conclusion 

Although the risks of HRT have been inflated by the popular press, there are potential side effects and risks from HRT that must be individualised and reduced by tailoring the therapy. Emerging data suggests fewer side effects with lower HRT doses, minimising or eliminating systemic progestogens, the use of non-oral routes in some women and the use of HRT in symptomatic women from near menopause. HRT can be offered to informed women for as long as they have debilitating symptoms but the data are not yet strong enough to advocate it for chronic disease prevention, except perhaps for osteoporosis prevention near menopause with the option of other effective fracture prevention treatments at a later age. The systematic reviews of HRT show that the main two start-up side effects are irregular uterine bleeding which is normal during the first few months of cHRT and breast tenderness when excessive oestrogen is used. The message is that the latest data on HRT do not warrant the fear and ultra-conservative approach adopted in 2002. Longer-term therapy is appropriate for women with long-term symptoms who are aware of the potential risks for their regimen in their personal circumstances. Individualised regimens can reduce the incidence of adverse outcomes. When HRT is initiated near menopause for symptom control and subsequent improved quality of life, there are likely to be additional bone, heart and possible cognitive benefits that outweigh the risks that are not significantly raised under the age of 60 years. After this age, women can try stopping therapy to see if their quality of life continues without therapy. However, some women have continuing symptoms even into their seventh decade and they should not be denied HRT if their therapy and risks are individualised, understood and not exaggerated.

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Competing interests 

Alastair MacLennan was Editor-in-Chief of Climacteric, The Journal of the International Menopause Society. Through the University of Adelaide he has received research funds and travel expenses from a variety of pharmaceutical companies.

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Further reading 

1. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial plus progestin. Maturitas. 2006;55:103–105
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