Monday, December 11 2000
For How Long Should A Woman Take Hormone Replacement Therapy?
By- Alastair H MacLennan, MBChB, MD, FRCOG, FRANZCOGDr. Alastair H MacLennan is Associate Professor, Obstetrics and Gynaecology, University of Adelaide, Australia. |
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The risks and benefits of long-term (eg >5 years) hormone replacement therapy (HRT) are uncertain because large long-term randomised placebo controlled trials [RCTs] are required to help settle this debate. These trials are expensive, difficult to run and can only examine a limited number of regimens and routes of HRT. Two such trials have recently commenced. The Women's Health Initiative (WHI) is US based and 27,000 women are receiving HRT in this study which also has placebo and dietary control groups. It is a 9 year study which started 2 years ago and has funding of nearly one billion US dollars. The other primary prevention study of HRT is the Women's International Study of long Duration Oestrogen after Menopause (WISDOM). It is a placebo controlled study of 10 years oestrogen, or oestrogen and progestogen therapy with a further 10 year follow-up of hard clinical end-points such as fracture, cardiac events, cancer, dementia, thromboembolism, quality of life and death. WISDOM will enrol 36,200 women internationally. In the UK, WISDOM is funded for 22,000 entrants and funding for a cohort of 2000 Australian women is currently being sought to contribute to this landmark trial. This collaboration will help validate the extrapolation of the results of WISDOM to the Australian population. This is an important opportunity as it is very unlikely that Australia could ever afford to fund such a large trial independently.
Until the results of WHI and WISDOM are known we can only guess at the potential primary effect of HRT on major post-menopausal morbidity and mortality from the much weaker designs of observational studies (cohort and case control). Before summarising the results of more than 100 such studies in the literature it is important to understand that these trials are not randomised and are open to bias and confounding. When the results of observational trials are expressed as relative risk, as a rule of thumb, there is less chance of a result being due to bias or confounding if the relative risk is more than halved ie. <0.5 or more than doubled ie. >2. The increased relative risk of lung cancer in smokers is 43.0 and thus the association is very strong. Similarly hot flushes are reduced to a RR of 0.2 in HRT users. Therefore, both results are likely to be causally related. Now compare these relative risks to the overall relative risks and benefits of long-term HRT seen in observational studies remembering that a relative risk of 1.0 suggests no effect either way.
Breast cancer
A reanalysis of the data from 51 observational studies by Beral et al (1997) showed a relative risk (RR) of 1.023 for each year of HRT use, and 1.35 for HRT use of 5 years or longer (average 11 years) 1. This small increase in RR (ie. under 2.0) could be due to detection bias eg. more mammography and GP checks in HRT users . HRT users also have more independent risk factors for breast cancer eg. higher social class, Western diet , fewer pregnancies, later first pregnancy, higher alcohol intake which could also account for changes in RR under 2 . Paradoxically, most observational studies show a significant reduction in mortality from breast cancer in HRT users. This finding is much less publicised in the media! However, if the increased prevalence proved true, this would equate to an extra 2 detected breast cancers per 1000 women who use HRT for 5 years and 6 over 10 years.
Currently it is not recommended that HRT users have increased mammography surveillance over non-users and there is no good evidence that HRT users with a family history of breast cancer further increase their risk compared to non-users with a similar history. Recent observational studies on the role of cyclical and continuous progestogens given with oestrogen therapy have not clarified if they have any effect on breast cancer rates.2,3
Bowel cancer
The most recent metaanalysis of 23 observational trials suggest a 20% reduction in colorectal cancer in postmenopausal women who have ever taken HRT ( RR=0.80,95%CI 0.72-0.92 )4 . However, again this result is open to the biases of non-randomisation and such an effect needs to be confirmed in long term RCTs .
Endometrial cancer
The RR of unopposed oestrogen for 10 years being associated with endometrial cancer is 9.0 and thus this is likely to be a true effect. Additional progestogen greatly reduces this risk but the degree of this protection is not accurately known. Currently the recommended regimen for women with a uterus is to move from cyclical to continuous low dose progestogen when clearly postmenopausal. Progestogens should be given cyclically before the menopause and for 1-2 years after menopause. Continuous therapy can be introduced after 4 years of cyclical therapy or when a woman is definitely post-menopausal. This reduces the amount of initial bleeding that is normally seen for several months on a combined continuous HRT regimen.
Thromboembolism
Current observational studies suggest that although this is a relatively rare potential complication, the absolute risk rises threefold from one in 10,000 to three in 10,000 in HRT users . A past history of thromboembolism after a thrombotic risk event prior to menopause is not an absolute contraindication to postmenopausal HRT but might require initial investigation for thrombophilia.5
Cardiovascular Disease
Observational studies suggest a 30-50% reduction (RR 0.5-0.7) in ischaemic heart disease (IHD) in HRT users. This is a potentially impressive effect given the high prevalence of IHD in later life. However, many have argued the potential bias in such studies of a "healthy user" effect.6 Against the latter argument is the finding of the greatest reduction in IHD in "unhealthy" HRT users with cardiovascular risk factors eg. smokers, hyperlipidaemia , hypertension. Animal studies, in vitro studies and a three year randomised placebo controlled trial (PEPI7) suggest plausible cardioprotective mechanisms for primary prevention of IHD in HRT users. Oestrogen is an antioxidant and calcium channel blocker, it improves the lipid profile, LP(a) and vascular reactivity. However, secondary prevention studies do not suggest that HRT can reverse the early risk of established IHD8. Currently HRT may be offered as a potential (but not established) primary cardioprotective agent in addition to other established drug therapies and lifestyle interventions in women with risk factors for IHD.
Stroke
HRT is not consistently associated with a change in the relative risk of stroke in observational studies.
Osteoporosis
More than half the untreated female population will experience an osteoporotic fracture often at considerable cost to the individual and the community. Short-term randomised control trials consistently show that HRT increases low bone density, and in normal women inhibits loss of bone after the menopause when used prophylactically. However, long-term randomised trials have still to be conducted to show that improved bone density converts into a major reduction in osteoporotic fractures, particularly at the hip. Improvements in surrogate endpoints for fracture in HRT users suggest that this will be one of the main benefits of long-term oestrogen if adherence to therapy is maintained. All therapies for osteoporosis require long-term compliance to achieve their effect.
In South Australia in 1997 median length of use in all women on HRT was 5 years and in women with a diagnosis of osteoporosis the median length of use was 6 years with a 70% continuance rate at 5 years 9.
Alzheimer's Dementia
A metaanalysis of 10 observational studies showed a significant reduction of this dementia in HRT users (RR 0.71) 10 but a recent secondary prevention RCT of 1 year therapy versus placebo did not suggest that HRT could reverse established disease 11. Although there are plausible neuroprotective mechanisms for HRT, long-term RCTs are awaited to see if HRT has a primary preventative role in this disease which is becoming more common with increasing longevity .
Other potential long-term risks still to be defined by long-term randomised controlled trials include increased risks of gall bladder and uterine surgery.
Other potential benefits may include a reduction in all the following: tooth loss, dry eyes, dry skin, arthritic symptoms, urge incontinence, frequency, nocturia, urinary tract infections, dry vagina, dyspareunia, memory loss and possibly some types of depression. All of these need to be assessed in trials such as WHI and WISDOM but currently where an individual finds on going symptom relief from HRT then long-term therapy may be appropriate for quality of life.
Current options for length of HRT use. With all the above caveats about the weaknesses of observational data, this data currently still has to be used in advising a woman about the potential risks and benefits of long-term HRT.
Until the results of WHI and WISDOM are available then general recommendations for length of therapy could be as follows.
- For menopausal symptom control . Up to 5 years therapy with the option of another 5 years if still symptomatic when weaned off HRT.
- For osteopenia/osteoporosis - 10-20 years therapy.
- For potential cardioprotection in women with cardiovascular risk factors - 10-20 years.
- For the potential prevention of Alzheimer's Disease. - life.
- For chronic urogenital problems responsive to HRT. - life.
Women's informed choice for long-term HRT should be based on unbiased information, explanation of the current data and its limitations and an understanding of her individual needs, risks and preferences. It should not be based on myth, selected information, vested interests in HRT or other products for the menopause and especially not on the lack of skill or knowledge of the adviser.
References:
1. Beral V for the Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997; 350: 1047-1059.
2. Schairer C, Lubin J, Troisi R et al. Menopausal Estrogen and Estrogen-Progestin Replacement Therapy and Breast Cancer Risk. JAMA 2000; 283: 485-491.
3. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000; 92: 328-32.
4. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999; 574-582.
5. Greer IA, Walker ID. Hormone replacement therapy and venous thromboembolism. Climacteric 1999;2:224-231.
6. Barrett-Connor E. Hormone replacement therapy. Br Med J 1998; 317:457-461.
7. Writing Group for the PEPI Trial. Effects of estrogen/progestin regimens on heart disease risk factors in postmenopausal women. J Am Med Assoc 1995; 273: 199-208.
8. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc 1998; 280: 605-613.
9. MacLennan A H, Wilson D H, Taylor A W. Hormone replacement therapies in women at risk of cardiovascular disease and osteoporosis in South Australia in 1997. Med J Aust 1999; 170: 524-527.
10. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. J Am Med Assoc 1998; 279: 688-695.
11. Mulnard RA, Cotman CW, Kawas C et al. Estrogen Replacement Therapy for treatment of mild to moderate Alzheimer Disease. J Am Med Assoc 2000; 283: 1007-15.
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