Estrogen Prophylaxis
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Recommendation:
Although routine postmenopausal estrogen replacement is not
recommended, estrogen therapy should be considered for
asymptomatic women who are at increased risk for
osteoporosis, who lack known contraindications, and who
have received adequate counseling about potential benefits
and risks (see Clinical Intervention). The role of exercise
and dietary calcium supplementation in preventing
osteoporosis is discussed in Chapters 49 and 50; see
Chapter 40 regarding screening for low bone mineral
content.
Burden of Suffering
It is estimated that 1.3 million osteoporosis-related
fractures occur each year in the United States.1 Most of
these injuries occur in postmenopausal women. It has been
estimated that about one-quarter of all women over age 60
have spinal compression fractures and about 15% of women
sustain hip fractures during their lifetime.2,3 Hip
fractures are associated with significant pain and
disability, decreased functional independence, and high
mortality. There is a 15-20% reduction in expected survival
in the first year following a hip fracture.4 Hip fractures
cost the United States over $7 billion each year in direct
and indirect costs.5 Important risk factors for
osteoporosis include advanced age, female sex, Caucasian or
Asian race, slender build, bilateral oophorectomy prior to
natural menopause, smoking, and alcohol abuse.
Efficacy of Chemoprophylaxis
There is good evidence from retrospective studies6-9 and
clinical trials10-17 that estrogen replacement can reduce
the rate of bone loss in postmenopausal women. Although it
is likely that this physiological effect on bone mineral
content can reduce the incidence of fractures and other
clinical measures of osteoporosis, prospective evidence
linking estrogen to fracture rates has been difficult to
obtain because of the long interval between the onset of
osteoporosis and the occurrence of symptoms. There is,
however, a large body of evidence from retrospective
studies,6,8,9,18 cross-sectional studies,19 cohort studies,
and nonrandomized clinical trials20,21 that estrogen
replacement is associated with a decreased rate of
fractures. These findings do not provide conclusive
evidence of efficacy, due to the potential influence of
selection bias, recall bias, and confounding in many of
these studies. It may be impractical, however, to carry out
randomized controlled trials of sufficient duration to
provide definitive evidence that estrogen replacement can
lower fracture rates.
The use of estrogen to prevent osteoporosis can also have
other benefits. Estrogen can reduce the incidence of
vasomotor flushes and vaginal atrophy. Perhaps the most
important benefit of estrogen, however, is its ability to
improve lipoprotein profiles; many studies in recent years
have demonstrated an association between the use of
estrogen and reduced mortality from coronary artery
disease.22-28 At the same time, there are potentially
important side effects associated with long-term use of
unopposed estrogen. Prolonged use of unopposed, conjugated
estrogens increases the risk of endometrial hyperplasia and
endometrial cancer.29-33 Although these tumors are usually
early-stage and minimally invasive at diagnosis, an
increased risk of disseminated endometrial cancer has been
documented.29,30 Combining estrogen with cycled progestins
may reduce the risk of cancer,34 but conclusive evidence of
an effect on endometrial cancer mortality is lacking.35 In
addition, some women may dislike the menstrual bleeding
produced by progestins and discontinue use of the drug.
There is inconsistent evidence regarding the reported
association between estrogen therapy and such diseases as
breast cancer and gallbladder disease.35-40
Effectiveness of Counseling
Few studies have examined the effectiveness of physician
counseling to use estrogen. There is evidence, however,
that compliance with estrogen therapy is generally poor
among postmenopausal women, in part because of the
perceived risk of developing cancer and unpleasant side
effects. One author, citing personal communications from
the investigators, reported that 20-30% of women in the
Massachusetts Women's Health Survey never had their
prescriptions filled because they were not convinced of the
benefits and safety of therapy; of those who began therapy,
20% discontinued the drug within nine months.41 Compliance
with estrogen replacement is often limited by the
inconvenience associated with daily administration. The
availability of transdermal estrogen and new dosage
regimens may offer potential means of reducing
inconvenience, but the effectiveness of alternative routes
of administration in enhancing long-term compliance has yet
to be proved.41
Recommendations of Others
The American College of Obstetricians and Gynecologists
recommends consideration of estrogen therapy in all
hypoestrogenic (including postmenopausal) women.42 A 1984
National Institutes of Health consensus development
conference recommended that estrogen therapy after
menopause should be considered in high-risk women who have
no medical contraindications and who are willing to adhere
to a program of careful follow-up.1 The Canadian Task Force
advises against widespread use of estrogen to prevent
osteoporosis, but recommends offering therapy to women who
appear to be at increased risk on an individual basis.43
Discussion
Although there is good evidence that estrogen therapy can
reduce bone loss in postmenopausal women, there is
insufficient evidence to recommend its routine
prescription. Definitive evidence that estrogen replacement
therapy can prevent bone fractures or other clinical
measures of osteoporosis requires a lengthy randomized
controlled trial that may be difficult to perform in the
future for logistical reasons. In the absence of such
evidence, it is difficult to determine with certainty
whether the benefits of estrogen replacement (e.g.,
preservation of bone mass, improved lipoprotein profiles
and cardiovascular mortality reduction, reduced menopausal
symptoms) outweigh its potential risks (e.g., endometrial
cancer) and inconvenience (e.g., vaginal bleeding, daily
administration) in all postmenopausal women. In some
asymptomatic women, however, such as those at increased
risk and those with early indications of low peak bone mass
(see Chapter 40), the benefit-risk ratio is likely to be
more favorable. It is especially important for such women
to receive counseling about potential benefits and risks so
that they can make an informed decision about therapy. The
perimenopausal period is an important time for such
decisions; the evidence is less clear regarding the
benefits of beginning estrogen treatment at older ages.44
Clinical Intervention
Although estrogen replacement is not recommended for all
postmenopausal women, estrogen therapy should be considered
in asymptomatic women who are at increased risk for
osteoporosis (e.g., Caucasian or Asian women, women with
low bone mineral content, those with a slender build, and
those with a history of early menopause or bilateral
oophorectomy prior to menopause) and who are without known
contraindications (e.g., history of undiagnosed vaginal
bleeding, active liver disease, thromboembolic disorders,
or hormone-dependent cancer). These patients should receive
information on the risks and consequences of osteoporotic
fractures and the risks and benefits of hormonal therapy.
All women should receive information about potential
alternatives for osteoporosis prevention such as
weight-bearing exercise (see Chapter 49) and dietary
calcium supplementation (see Chapter 50). Women consenting
to estrogen therapy should be counseled about the various
estrogen and progestin preparations and routes of
administration that are available. One common regimen is
0.625 mg conjugated equine estrogen on days 1-25 (or daily)
with the addition of 5-10 mg medroxyprogesterone acetate
during the last 12 days of the cycle. Dosages should be
modified to reduce side effects such as nausea, headache,
breakthrough bleeding, weight gain, and breast tenderness.
Note: See the relevant U.S. Preventive Services Task Force
background paper: Mann K, Wiese WH, Stachencko S.
Preventing postmenopausal osteoporosis and related
fractures. In: Goldbloom RB, Lawrence RS, eds. Preventing
disease: beyond the rhetoric. New York: Springer-Verlag (in
press).
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