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Postmenopausal
Hormone-Replacement Therapy — Time for a Reappraisal?
In
this issue of the Journal, Grodstein and colleagues1
present important data from a large study of the risks and
benefits associated with postmenopausal hormone-replacement
therapy. Like previous investigators, they found a significantly
reduced risk of death from all causes among recent hormone users.
This reduction in mortality is the consequence of a profound
decrease in the risk of death from coronary heart disease and a
somewhat smaller reduction in mortality from cancer, although this
reduction was not evident for all types of cancer. The study showed
that the reduction in mortality from cardiovascular disease and
cancer was probably not due to patterns of selective prescribing
of estrogens for women without these diseases or to the
discontinuation of hormone therapy at the onset of the fatal disease.
It is less clear that these issues of bias were addressed with
respect to other causes of death. In addition, questions remain
about the extent to which reduced mortality from cancer may
reflect earlier disease detection among hormone users.
Furthermore, since the study considered only exposures before the
development of fatal diseases, it did not address the issue of
hormone use after the diagnosis of disease, a particularly important
issue with regard to cardiovascular disease.
One strength of this study is the assessment of mortality in
relation to both how recently and for how long hormones were
used. The protective effect of hormones was lost five years
after the discontinuation of use, and extended exposure provided
no additional benefit among current users. In fact, there was
some attenuation of the protective effect with long duration of
use, which was attributable primarily to a 43 percent increase in
deaths from breast cancer among women who had used hormones for 10 or
more years. However, the proportion of deaths due to breast cancer
was higher in the study cohort than in the general population,
possibly limiting the generalizability of the results.
Mortality from breast cancer was reduced overall in this latest
study, a finding consistent with those of other studies, but
the increased mortality among current users who had been taking
hormones for 10 or more years is a matter of concern, particularly
given that some studies have shown an increased incidence of
breast cancer among long-term or current users.2,3,4
A curious finding was that short-term users had a reduced risk of
death from breast cancer, which more than offset the increased
risk in long-term users. It is possible that the inconsistency
in the results for short- and long-term users reflects the small
number of deaths in each category. However, if the adverse effect
of long-term hormone use on breast-cancer mortality is confirmed
by additional research, this will argue against the notion that
hormones predispose women to low-risk breast tumors, as suggested
by studies showing better survival5
and diagnosis of less advanced disease3
in hormone users than in nonusers.
The study provides important data on the increasingly popular
regimen of estrogens in conjunction with progestins, showing
substantial reductions in overall mortality among users of the
combined regimen as well as users of estrogens alone. These
results indirectly address the concern aroused by experimental
data that progestins may diminish the apparently cardioprotective
effect of estrogen therapy. This issue was addressed more directly
in a recent report from the Nurses’ Health Study,6
which showed a reduction in coronary heart disease among users of
estrogens with progestins equal to or greater than that among users
of estrogens alone. It would also be of interest for studies to
assess mortality from breast cancer in relation to the use of
estrogen combined with progestin, particularly because there is
some concern, although based on limited2,4
and inconsistent7
epidemiologic data, that combined therapy may increase the incidence
of breast cancer more than estrogen alone. As the number of
deaths from endometrial cancer accrues in this cohort, it will
also be important to assess the mortality from this disease,
given evidence that the addition of progestins may not completely
counteract the adverse effect of estrogens on the endometrium.8
Given that a white woman’s cumulative absolute risk of death from
the ages of 50 to 94 years has been estimated to be 31 percent from
coronary heart disease, 2.8 percent from breast cancer, and 2.8
percent from hip fracture,9
the benefits of estrogen use appear to far outweigh the risks.
Notably, in this study long-term hormone users had a 20 percent
reduction in mortality. However, for many women the benefits of
hormone use may not compensate for the fear of acquiring breast
cancer and living with its repercussions. Furthermore, in some women
at low risk for cardiovascular disease but at high risk for
breast cancer, the benefits of hormone therapy may not outweigh
the risks.10
Unfortunately, the issues of risks versus benefits do not easily lend
themselves to simple formulas for calculating who should take
estrogen and for how long. Decisions need to be personal ones and
should involve detailed discussions between a woman and her
physician. These discussions should consider individual risk
profiles,10
such as the one discussed in the article by Grodstein et al. However,
a number of unresolved questions about individualized risks remain.
Although the latest findings show the greatest reductions in
hormone-associated mortality among women at high risk for coronary
disease, previously published findings from this cohort showed
hormone use to result in similar reductions in major coronary disease
regardless of a woman’s risk-factor profile.6
The study addresses an important question by showing that hormone
users with a family history of breast cancer are not at any greater
risk of death than hormone users without such a history. However, in
terms of making decisions about the risk of breast cancer, it might
be more useful to evaluate breast-cancer mortality, specifically
assessing hormone-related risks for women at high risk for breast
cancer as compared with those at low risk and considering not only
the factors mentioned but also others known to have a major impact on
the risk of breast cancer (e.g., reproductive behavior and benign
breast disease).
Given the findings that hormone use is associated with reduced
mortality for multiple causes of death11
and that there are marked lifestyle differences between hormone users
and nonusers,12
there continue to be lingering questions regarding the extent
to which reductions in mortality are due to hormone use itself
as opposed to the characteristics of the user. Some of the unresolved
issues must await the results of ongoing intervention trials of
menopausal hormones. However, since these trials may not continue
long enough to accrue large numbers of patients in whom cancer
develops, it will also be important to evaluate data from large
observational studies. If the protective effect of long-term use
continues to dissipate with time and adverse effects on breast-cancer
mortality are confirmed, the optimal duration of hormone-replacement
therapy will need to be reconsidered. That the beneficial effects of
hormones are dependent on recent use raises questions about when to
initiate use. It is encouraging that hormone use begun later in life
offers bone-conserving benefits nearly equal to those conferred by
use initiated earlier.13
Furthermore, it is important, as Grodstein et al. and others
have pointed out, that other means of reducing the incidence of
cardiovascular diseases and osteoporosis have been identified.
Physical activity is one such approach,14
of interest in that it may also reduce the incidence of breast
cancer.15
Although further research is needed to clarify the relative
benefits of various interventions as compared with
hormone-replacement therapy, it may now be the time to question
seriously whether hormone-replacement therapy should be prescribed
for life or whether for some women, it should be more restricted in
duration and combined with other effective disease-prevention
techniques.
Louise A. Brinton, Ph.D.
Catherine Schairer, Ph.D.
National Cancer Institute
Bethesda, MD
20892
References
- Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal
hormone therapy and mortality. N Engl J Med 1997;336:1769-1775.[Abstract/Full Text]
- Bergkvist L, Adami H-O, Persson I, Hoover R, Schairer C. The risk
of breast cancer after estrogen and estrogen-progestin replacement. N Engl J
Med 1989;321:293-297.[Abstract]
- Brinton LA, Hoover R, Fraumeni JF Jr. Menopausal oestrogens and
breast cancer risk: an expanded case-control study. Br J Cancer
1986;54:825-832.[Medline] - Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens
and progestins and the risk of breast cancer in postmenopausal women. N Engl J
Med 1995;332:1589-1593.[Abstract/Full Text]
- Bergkvist L, Adami H-O, Persson I, Bergstrom R, Krusemo UB.
Prognosis after breast cancer diagnosis in women exposed to estrogen and
estrogen-progestogen replacement therapy. Am J Epidemiol 1989;130:221-228.[Abstract]
- Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal
estrogen and progestin use and the risk of cardiovascular disease. N Engl J
Med 1996;335:453-461. [Erratum, N Engl J Med 1996;335:1406.][Abstract/Full Text]
- Newcomb PA, Longnecker MP, Storer BE, et al. Long-term hormone
replacement therapy and risk of breast cancer in postmenopausal women. Am J
Epidemiol 1995;142:788-795.[Abstract]
- Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial
cancer in relation to use of oestrogen combined with cyclic progestagen
therapy in postmenopausal women. Lancet 1997;349:458-461.[CrossRef][Medline] - Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles’,
or vertebral fracture and coronary heart disease among white postmenopausal
women. Arch Intern Med
1989;149:2445-2448.[Abstract]
- Col NF, Eckman MH, Karas RH, et al. Patient-specific decisions
about hormone replacement therapy in postmenopausal women. JAMA
1997;277:1140-1147.[Abstract]
- Schairer C, Adami H-O, Hoover R, Persson I. Cause-specific
mortality in women receiving hormone replacement therapy. Epidemiology
1997;8:59-65.[Medline] - Matthews KA, Kuller LH, Wing RR, Meilahn E, Plantinga P. Prior to
use of estrogen replacement therapy, are users healthier than nonusers? Am J
Epidemiol 1996;143:971-978.[Abstract]
- Schneider DL, Barrett-Connor EL, Morton DJ. Timing of
postmenopausal estrogen for optimal bone mineral density: the Rancho Bernardo
Study. JAMA 1997;277:543-547.[Abstract]
- Kushi LH, Fee RM, Folsom AR, Mink PJ, Anderson KE, Sellers TA.
Physical activity and mortality in postmenopausal women. JAMA
1997;277:1287-1292.[Abstract]
- Thune I, Brenn T, Lund E, Gaard M. Physical activity and the risk
of breast cancer. N Engl J Med 1997;336:1269-1275.[Abstract/Full Text]
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This article has been cited by other
articles:
- Csizmadi, I., Benedetti, A., Boivin, J.-F., Hanley, J. A., Collet, J.-P.
(2002). Use of postmenopausal estrogen replacement therapy from 1981 to 1997.
Can Med Assoc J 166: 187-188 [Full
Text] - KOUKOULIS, G. N. (2000). Hormone Replacement Therapy and Breast Cancer
Risk. Annals NYAS Online 900: 422-428 [Abstract]
[Full
Text] - Liu, Y., Ding, J., Bush, T. L., Longenecker, J. C., Nieto, F. J., Golden,
S. H., Szklo, M. (2001). Relative Androgen Excess and Increased Cardiovascular
Risk after Menopause: A Hypothesized Relation. Am. J. Epidemiol. 154:
489-494 [Abstract]
[Full
Text]
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