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Making decisions about hormone replacement therapyVaccination News Home Page subscribe Vaccination NewsLetter http://bmj.com/cgi/content/full/326/7384/322?etoc
Clinical reviewMaking decisions about hormone replacement therapyJanice Rymer a Guy's, King's and St Thomas's School of Medicine, Guy's and St Thomas's Hospital Trust, London SE1 7EH, b Department of Family Medicine, Queen's University, Kingston, Ontario, Canada, c Department of General Practice and Primary Care, Guy's, King's and St Thomas's School of Medicine, King's College London SE11 6SP Correspondence to: J Rymer, Department of Obstetrics and Gynaecology, St Thomas's Hospital, London SE1 7EH janice.rymer@kcl.ac.uk Many women will at some stage consider taking hormone replacement therapy, but uncertainty about the risks and benefits makes this decision difficult Since hormone replacement therapy was introduced 70 years ago, a steady flow of studies has produced evidence of both harmful and beneficial effects. Recent British studies have shown that 60% of women aged 51-7 years have taken hormone replacement therapy,1 with 45% having tried it by the time they are 50.2 In the United States, about 38% of postmenopausal women take hormone replacement therapy. In 2000, 46 million prescriptions were written for Premarin (conjugated equine oestrogens), making it the second most frequently prescribed drug in the United States.3 Women are increasingly encouraged to participate in making decisions about
hormone replacement therapy. However, the complexity and uncertainty
of information about the treatment can make it difficult for women to
make a decision, increasing their reliance on medical advice.4
The publication of the heart and oestrogen-progestin replacement
study (HERS)5 and women's health initiative (WHI)6
study, both of which found adverse effects, has added to the confusion.
In this article, we define who should be offered hormone replacement
therapy and why, describe the reasons why women may wish to take
hormone replacement therapy, and clarify the advantages and disadvantages
of treatment.
We based this article on recent publications on hormone replacement therapy
and our extensive experience in running a menopause clinic,
prescribing hormone replacement therapy, and researching into hormone
replacement therapy.
The main reasons for prescribing hormone replacement therapy are relief of
menopausal symptoms and prevention or management of osteoporosis.
Some evidence also exists that it may have a role in primary and
secondary prevention of cardiovascular disease, prevention of
colorectal cancer, and prevention of Alzheimer's disease. Hormone
replacement therapy seems to be associated with an increased risk of
breast cancer, myocardial infarction, cerebrovascular disease, and
thromboembolic disease.
Experiences of menopausal symptoms vary widely and have been found to relate to factors such as social class,7 ethnicity,8 and culture.9 The most common reason motivating women to take hormone replacement therapy is the relief of menopausal symptoms. 2 10-12 Although women report that hormone replacement therapy improves various
menopausal symptoms,13 randomised clinical trials
have proved that it is effective for only vasomotor14
and urogenital symptoms.15 A "domino"
effect may occur
After the age of 35 years, men and women start to lose around 1% of bone mass
each year. However, bone loss is accelerated during the first three
to four years after the menopause. A third of women over the age of
50 years sustain a fracture, with osteopenia a major risk factor.17
Women with specific risk factors (box) should be offered bone density
screening (preferably dual x ray absorptiometry) and those
with a low bone mass offered hormone replacement therapy or other
antiresorptive treatment. Follow up bone density measurements can be
used to adjust the dose of hormone replacement therapy and ensure
women maintain adequate bone mass.
Randomised controlled trials have shown that hormone replacement therapy reduces bone loss at clinically relevant sites such as the spine (reduced by 50%) and neck of femur (by 30%). In addition, a review of randomised trials reported a significant reduction in fractures in women taking hormone replacement therapy. This effect, however, may be less in women older than 60.18 The WHI study was the first randomised controlled trial to show a reduction in hip fracture with hormone replacement therapy.6 Bone loss resumes within a year after stopping hormone replacement therapy, however, and bone turnover rises to the level of that in untreated women within three to six months. Non-hormonal therapies such as bisphosphonates and selective oestrogen
receptor modulators are as effective as hormone replacement therapy
for preventing fractures. These are a good treatment for women with
low bone mineral density who do not have problematic hypo-oestrogenic
symptoms, have contraindications to hormone replacement therapy, or
do not wish to take it.
Cardiovascular disease rarely affects women before the menopause, strongly implicating oestrogen deficiency in the aetiology of the disease. Observational studies have reported that oestrogen decreases morbidity and mortality from coronary heart disease by 30-50%.19 This benefit is reduced, however, by the addition of progestogens, which are needed to prevent endometrial disease.20 Indeed, the WHI and HERS double blind, randomised, placebo controlled trials have shown that continuous treatment with 0.625 mg of conjugated equine oestrogens plus 2.5 mg of medroxyprogesterone increases the risk of heart disease events by 29% (37 v 30 per 10 000 person years) and stroke by 41% (29 v 21 per 10 000 person years). 5 6 21 The HERS study investigated the risk of events among 2763 postmenopausal women with documented coronary heart disease.5 During a mean of 4.1 and 6.8 years of follow up there were no significant differences between the hormone and placebo groups in coronary heart disease events (non-fatal myocardial infarction plus coronary heart disease related death) or in any secondary cardiovascular outcome.22 However, further analysis showed a significant time trend, with more coronary heart disease events in the hormone group than in the placebo group during the first year of treatment and fewer in years 3-5. The WHI study examined the effect of hormone replacement therapy in 16 608 healthy menopausal women.6 The study had to be stopped prematurely when the risk of invasive breast cancer exceeded the stopping boundary. The primary outcome was coronary heart disease (non-fatal myocardial infarction and death from coronary heart disease) with invasive breast cancer as the primary adverse outcome. Women in the oestrogen-progestogen group had an absolute excess risk of 7/10 000 person years for coronary heart disease events and 8/10 000 for stroke. Most of the excess events were non-fatal. Another arm of the study continues to compare oestrogen alone with placebo, and this will help determine whether the progestogen is causing the harm. The recommendation after both these studies was that postmenopausal hormone
replacement therapy should not be used for reducing risk of coronary
heart disease. The results of these studies cannot be extrapolated to
other forms and routes of administration of hormone replacement
therapy since different progestogens have significantly different
effects.
Studies generally show an increased risk of deep vein thrombosis and pulmonary embolus in women taking hormone replacement therapy.23-25 The absolute risk in current users is small, with estimates of 16 and 23 excess cases per 100 000 women a year for all venous thromboembolism and 6 per 10 000 women a year for pulmonary embolism. Women taking hormone replacement therapy have twice the risk of venous thromboembolism compared with non-users. The increase in risk seems to be greater in the first year of use, with an
odds ratio of 4.6 (95% confidence interval 2.5 to 8.4) during the
first six months. Hormone replacement therapy may therefore be
unmasking an underlying thrombophilic tendency. The risks of venous
thromboembolism with hormone replacement therapy are likely to be
greater in women with predisposing factors such as a family history
of thromboembolic disease, severe varicose veins, obesity, surgery,
trauma, or prolonged bed rest, and age is an important risk
factor.
Observational studies have consistently suggested that hormone replacement
therapy reduces the risk of colorectal cancer.26
The WHI study, however, was the first randomised controlled trial
to confirm this, reporting six fewer colorectal cancers each year
in every 10 000 women taking hormone replacement therapy compared
with the placebo group.6 The mechanisms
behind this reduction in colorectal cancer are not clear.
A serious concern for women taking long term hormone replacement therapy is the reported increased risk of breast cancer.27 Several epidemiological studies have reported an increased risk of breast cancer, and the risk is higher with oestrogen-progestogen combinations than with oestrogen alone. A large meta-analysis of data from 51 observational studies reported that the risk of breast cancer increased by 2.3% for every year of use of hormone replacement therapy.28 This increased risk does not become significant unless hormone replacement therapy is taken for more than five years, when the relative risk is 1.35. The cumulative incidence of breast cancer in women aged 50-70 years in women who have never used hormone replacement therapy is about 45 cases per 1000 women. The excess risk translates to two extra cases of breast cancer for every 1000 women taking hormone replacement therapy for five years, six extra cases for every 1000 women taking it for 10 years, and 12 extra cases for every 1000 taking it for 15 years. Although the incidence of breast cancer increased over time, the study did not show an increase in mortality. Possible reasons for this include increased health surveillance and a tendency for less aggressive, well differentiated tumours in women taking hormone replacement therapy. The risk of breast cancer falls after stopping hormone replacement therapy and returns to baseline within five years. Because the WHI study stopped early, it could not examine the risk of death
from breast cancer. However, it did confirm the excess risk of breast
cancer with hormone replacement therapy. There was a 15% increase in
invasive breast cancer in women taking oestrogen plus progestogen for
less than five years and a 53% increase in those taking it for more
than five years. The study concluded that for every 10 000 women
taking oestrogen and progestogen, there would be eight more cases of
invasive breast cancer a year.
The increased incidence of endometrial hyperplasia and endometrial cancer
associated with unopposed hormone replacement therapy has been
established since the 1970s. Progestogen decreases the excess risk of
endometrial cancer but protection decreases with long term use of
sequential regimens, and the risk is significantly increased after
five years of use.29-31 The continuous progestogen
regimens correct complex hyperplasia that arises during sequential
therapy and keeps the endometrium suppressed in the longer term.32
Although concerns have been raised about an association between hormone
replacement therapy and ovarian cancer, studies have not shown a
consistent increase in risk. For example, a recent study reported an
increased risk of ovarian cancer in women taking postmenopausal
oestrogen replacement therapy for more than 10 years (relative risk
1.8, 95% confidence interval 1.1 to 3.0) but no increase in risk of
ovarian cancer among users of continuous combined hormone replacement
therapy.33
The principles of prescribing require that drugs are efficacious, acceptable, and cost effective and have a reasonable risk-benefit ratio. The figure shows a flowchart to help decide who should be offered hormone replacement therapy.
Symptomatic perimenopausal women
Symptomatic postmenopausal women
Women with a uterus can take sequential hormone replacement therapy (oestrogen continuously and progestogen for 12-14 days of each month), continuous combined oestrogen-progestogen, or oestrogen plus the progestogen containing intrauterine system, which delivers progestogen locally to the endometrium. Women who opt for oestrogen replacement therapy plus the intrauterine system may avoid the apparent negative effects of progestogen on the breast and cardiovascular system. The intrauterine system is not licensed in Britain for this indication, but there is considerable evidence of the safety and efficacy, and it is widely used for this purpose, particularly in Scandanavia.34
Symptomatic women with premature menopause
Women with urogenital symptoms
Women with temporary ovarian failure
Women who should not be offered hormone replacement therapy
Competing interests: JR has received research funding from Organon, consultancy fees from Organon, Wyeth, Janssen-Cilag, and Pfizer, and been sponsored to attend conferences by several drug companies.
© 2003 BMJ
Publishing Group Ltd
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Sources and
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for
example, relieving hot flushes may improve sleep, which may improve
mood. In addition, oestrogen has been found to improve quality of
life in the short term.
oestradiol vaginal tablets in the treatment of atrophic vaginities: a double
blind placebo controlled study. Eur J Obstet Gynaecol Reprod Biol
1992; 44: 137-144