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Long-term hormone replacement therapy |
Key words: menopause, cancer, oestrogens, osteoporosis.
(Aust Prescr 2000;23:90-2)
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Introduction
The risks and benefits of taking hormone replacement therapy (HRT)
for more than five years are uncertain. There are no large long-term randomised
placebo-controlled trials to guide the duration of therapy. Large trials
are expensive, difficult to run and can only examine a limited number
of regimens and routes of HRT.
Until the results of large trials (see box)
are reported we can only guess at the potential primary effect of HRT
on major postmenopausal morbidity and mortality from the much weaker designs
of observational studies (cohort and case control). These trials are not
randomised and are open to bias and confounding. When the results of observational
trials are expressed as relative risk, there is generally less chance
of a result being due to bias or confounding if the relative risk is more
than halved (<0.5) or more than doubled (>2.0). The increased relative
risk of lung cancer in smokers is 43.0 and thus the association is very
strong. Hot flushes are reduced by HRT to a relative risk of 0.2. Both
results suggest the findings are likely to be causally related. A relative
risk of 1.0 suggests no effect either way.
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Two large randomised controlled trials have recently commenced. The Women's Health Initiative includes 27 000 American women who will receive HRT or placebo treatment. It is a nine-year study which started two years ago with funding of nearly US $1 billion. 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 women taking oestrogen, or oestrogen and progestogen for 10 years with a further 10-year follow-up of clinical end-points such as fracture, cardiac events, cancer, dementia, thromboembolism, quality of life and death. WISDOM will enrol 36200 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 important trial. This collaboration will help validate the extrapolation of the results of WISDOM to the Australian population. |
Breast cancer
A reanalysis of the data from 51 observational studies showed a relative
risk of 1.023 (95% CI* 1.01-1.04) for each year of HRT
use. The relative risk for HRT use of five years or longer (average 11
years) was 1.35 (95% CI 1.21-1.49).1 These
small increases in relative risk (i.e. under 2.0) could be due to detection
bias, for example the HRT users could have had more breast examinations
and mammograms. HRT users also have more independent risk factors, such
as higher social class, Western diet, fewer pregnancies, later first pregnancy,
and a higher alcohol intake, which could also account for small changes
in the relative risk of breast cancer. However, if the increased risk
is real it would equate to an extra two detected breast cancers per 1000
women who use HRT for five years. Paradoxically, most observational studies
show a significant reduction in deaths from breast cancer in HRT users.
Selection and detection bias can confound all these results.
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. Women taking HRT do not need to have mammography more often than
other women.
Recent observational studies on the role of added cyclical and continuous
progestogens given with oestrogen therapy have not clarified if these
regimens have any effect on breast cancer rates.2,3
The relative risks were again small in both studies with overlap
of the confidence intervals for oestrogen alone versus oestrogen/progestogen
regimens. Thus, no recommendations can yet be made as to whether added
progestogens influence breast cancer risk.
Bowel cancer
The most recent meta-analysis of 23 observational trials suggests
that in postmenopausal women who have ever taken HRT the relative risk
is 0.80 (95% CI 0.72-0.92).4 This is
a 20% reduction in colorectal cancer, however this result is open to the
biases of non-randomisation. The effect needs to be confirmed in long-term
randomised placebo-controlled trials.
Endometrial cancer
The relative risk that taking unopposed oestrogen for 10 years causes
endometrial cancer is 9.5 (95% CI 7.40-12.30) and so 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 take oestrogen and cyclical
progestogens before the menopause and for 1-2 years after menopause.
Continuous combination therapy can be introduced after four years of cyclical
therapy or when the woman is definitely postmenopausal. This reduces the
amount of initial bleeding that is normally seen for several months when
commencing a combined continuous HRT regimen.
Thromboembolism
Current observational studies suggest that although this is a relatively
rare potential complication, the absolute risk rises from 1 in 10 000
to 3 in 10 000 in HRT users (relative risks in four studies ranged from
2.1- 6.9). A past history of thromboembolism before the menopause is not
an absolute contraindication to postmenopausal HRT, but might prompt the
prescriber to consider testing for thrombophilia.5
Cardiovascular disease
Observational and animal studies suggest a potential benefit for HRT.
A recent meta-analysis of these epidemiological studies reports a relative
risk of 0.70 (95% CI 0.65-0.75) for oestrogen therapy alone and 0.66
(0.53-0.84) for combined HRT.6 However,
many researchers argue that the studies have the potential bias of a 'healthy
user' effect. A three-year randomised placebo-controlled trial (PEPI)7
has suggested a potential benefit in the primary prevention of ischaemic
heart disease. Secondary prevention studies do not suggest that HRT can
reverse the early risk of established ischaemic heart disease.8
Currently HRT may be offered to women with risk factors as a potential
(but not established) primary cardioprotective agent to complement other
established drug therapies and lifestyle changes.
Stroke
HRT was not consistently associated with a change in the relative
risk of stroke in observational studies.
Osteoporosis
Short-term randomised controlled trials consistently show that HRT
improves low bone density, and when used prophylactically it inhibits
loss of bone after the menopause. However, long-term randomised trials
are still needed to show that improved bone density results in a major
reduction in osteoporotic fractures, particularly at the hip. Improvements
in surrogate end-points suggest that a reduced risk of fractures will
be one of the main benefits of taking oestrogen for many years.
All therapies for osteoporosis require long-term compliance to achieve
their effect. In South Australia in 1997 the median length of use in all
women on HRT was five years with 70% continuance rate at five years. In
women with a diagnosis of osteoporosis the median length of use was six
years.9
Alzheimer's dementia
A meta-analysis of 10 observational studies showed a reduction of
this dementia in HRT users. The relative risk was 0.71 (CI 0.52-0.98).10
Although there are plausible neuroprotective mechanisms for HRT, long-term
randomised placebo-controlled trials are awaited to see if HRT has a primary
preventative role in this disease which is becoming more common with increasing
longevity. A recent secondary prevention trial does not suggest that HRT
can reverse established disease.11
Other risks and benefits
Potential long-term risks still need to be defined by long-term randomised
controlled trials. They include increased risks of gall bladder and uterine
surgery.
Other potential benefits may include a reduction in 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 large trials,
but if a woman experiences sustained symptom relief from HRT then long-term
therapy may be appropriate to maintain her quality of life.
Current options for length of HRT use
With all the caveats about the weaknesses of observational data, these
data are all we can use when advising a woman about the potential risks
and benefits of long-term HRT. Until the results of the Women's Health
Initiative and WISDOM are available it is not possible to make general
recommendations for the duration of treatment. Probably, for menopausal
symptom control, up to five years therapy is appropriate, with the option
of another five years if still symptomatic when weaned off HRT. Longer
therapy would be necessary for other potential indications such as the
prevention of cardiovascular disease, dementia, some urological problems
and osteoporosis. Phytoestrogens have yet to be shown in published rigorous
scientific trials to be of greater benefit for menopausal symptoms than
a placebo or to prevent osteoporotic fractures and cardiovascular events.
A woman'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, Bull D, Doll R, Key T, Peto
R, Reeves G, et al. 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;350:1047-59.
2. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton
L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy
and breast cancer risk. JAMA 2000;283:485-91.
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;106:574-82.
5. Greer IA, Walker ID. Hormone replacement therapy and
venous thromboembolism. Climacteric 1999;2:224-31.
6. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998;19:55-72.
7. Writing Group for the PEPI Trial. Effects
of estrogen orestrogen/progestin regimens on heart disease risk factors
in postmenopausal women [published erratum appears in JAMA 1995;274:1676].
JAMA 1995;273:199-208.
8. Hulley S, Grady D, Bush T, Furberg C, Herrington D,
Riggs B, et al. Randomized trial of estrogen plus progestin for secondary
prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.
9. MacLennan AH, Wilson DH, Taylor AW. Hormone replacement
therapies in women at risk of cardiovascular disease and osteoporosis
in South Australia in 1997. Med J Aust 1999;170:524-7.
10. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998;279:688-95.
11. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA 2000;283:1007-15.
E-mail: alastair.maclennan@adelaide.edu.au
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