Hormone Replacement Therapy: Real Concerns and False Alarms
Avrum Z. Bluming, MD, and Carol Tavris, PhD
Abstract: From 2002 to 2008, reports from the Women’s Health Initiative
(WHI) claimed that hormone replacement therapy (HRT) signiﬁcantly in-
creased the risks of breast cancer development, cardiac events, Alzheimer
disease, and stroke. These claims alarmed the public and health professionals
alike, causing an almost immediate and sharp decline in the numbers of
women receiving HRT. However, the actual data in the published WHI
articles reveal that the ﬁndings reported in press releases and interviews of
the principal investigators were often distorted, oversimpliﬁed, or wrong.
This review highlights the history of research on HRT, including a timeline of
studies that have or have not found a link between HRT and breast cancer;
discusses how to distinguish important, robust ﬁndings from those that are
trivial; closely examines the WHI ﬁndings on HRT and breast cancer, most of
which are weak or statistically insigniﬁcant; reviews the current thinking about
possible links of HRT with cardiovascular disease and cognitive functioning;
and reports research on the beneﬁts of HRT, notably relief of menopausal
symptoms, that affect a woman’s quality of life. On these complicated matters,
physicians and the public must be cautious about accepting “ﬁndings by press
release” in determining whether to prescribe or take HRT.
Key Words: hormone replacement therapy (HRT), estrogen, breast cancer,
women’s health initiative (WHI), risk assessment
(Cancer J 2009;15: 93–104)
Hormone Replacement Therapy (HRT)
is the term used for the
administration of estrogen, or estrogen plus progestin, to
women who have reached menopause. Estrogen is most commonly
given with progestin to women who still have a uterus, because as
early as 1975 investigators had found that estrogen, taken alone,
increases the incidence of uterine cancer.
This increased risk is
eliminated when progestin is added.
Estrogen replacement therapy
(ERT) alone is thus generally given only to women who have had
The majority of American women do not take any form of
HRT during or after menopause; of those who do, most take it for
fewer than 5 years.
A minority of women—percentages vary
across community studies—take HRT for the rest of their lives. HRT
is highly effective in alleviating the most common menopausal
symptoms, including hot ﬂashes, night sweats, emotional lability,
palpitations, insomnia, uncomfortable and frequent urination, and
painful sexual intercourse.
Some women who are at high risk of
osteoporosis are also prescribed HRT, because estrogen decreases
the incidence of osteoporotic hip fracture by 25% to 50%.
Given that alternative medications— bisphosphonates such as Foso-
max, Actonel, and Boniva— offer a similar protective beneﬁt, most
physicians no longer recommend using hormones simply to prevent
hip fracture. These alternatives, however, can have unpleasant side
effects, including esophageal and stomach irritation and, in rare
cases, jaw-bone damage (osteonecrosis).
For decades, researchers, physicians, and women’s health
advocates have debated the risks and beneﬁts of estrogen, with or
without progestin. In the 1950s and 1960s, when Ayerst Laborato-
ries aggressively began marketing their estrogen preparation, Pre-
marin, supplementary hormones for postmenopausal women were
heralded as a panacea that would, in the seductive words of New
York gynecologist Robert Wilson, keep women “feminine forever.”
Yet, by the 1980s, various critics began arguing that supplementary
hormones were a serious and unnecessary risk to women’s health.
The critics’ greatest concern was breast cancer, a disease that many
women understandably fear (although heart disease causes far more
deaths than breast cancer does).
In July 2002, with the ﬁrst publication of ﬁndings from the
Women’s Health Initiative (WHI), headlines across the country
began trumpeting the dangers of HRT—not only breast cancer but
also heart disease and stroke.
The news was particularly alarming
because the WHI is the largest prospective study in which women
were randomized to take hormones or a placebo and then followed
over time. An earlier prospective, randomized, double-blind study
had found no increased risk of breast cancer in women on HRT,
even after 22 years, but this small study never made headlines.
WHI research has cost nearly a billion dollars; the investigators
consist of eminent physicians, statisticians, and epidemiologists
across the country, and the ﬁndings have been published in medi-
cine’s most prestigious journals. Accordingly, the WHI’s ﬁndings
received, and continue to receive, worldwide attention. It is no
wonder that its claims of the dangers of HRT caused the prescription
rate for HRT to fall by some 50%.
DATA DREDGING, RISK REPORTING, AND OTHER
PROBLEMS IN RESEARCH
Should women who have menopausal symptoms deny them-
selves its beneﬁts, whether in the short term or over many years,
because they fear breast cancer, heart disease, or stroke? Are their
concerns warranted by the data? When we took a close look at the
ﬁndings in the published WHI articles, placing them in the context
Received for publication January 5, 2009; accepted January 27, 2009.
Reprints: Avrum Z. Bluming, MD, 16133 Ventura Boulevard, Suite 470, Encino,
CA 91436. E-mail: email@example.com.
Dr. Bluming is a Master of the American College of Physicians, a Clinical
Professor of Medicine at the University of Southern California, a former
senior investigator for the National Cancer Institute and an oncologist in
private practice. Dr. Tavris is a social psychologist, writer, and lecturer, fellow
of the Association for Psychological Science, coauthor of two leading psy-
chology textbooks and, most recently, of Mistakes Were Made (But Not by
Me) (with Elliot Aronson). The reader should know that neither of us has any
vested interest in defending the pharmaceutical industry nor have we accepted
compensation for writing this article; indeed, one of us (CT) has been a
vociferous critic of the industry’s often-biased research.
Copyright © 2009 by Lippincott Williams & Wilkins
In this article, we use the term “HRT” for hormone replacement therapy because that
has been the accepted term in the literature for many years; “hormone therapy” is
too vague and broad and would apply to hormones given to women or men for
any reason. We agree, however, with critics concerned that the word “replace-
ment” implies recommendation of this treatment. Our own preference would be
to replace HRT with “menopausal hormone therapy.”
Progestin is the generic term for molecules that bind to and activate progesterone
receptors; it includes progesterone and synthetic derivatives such as medroxy-
The Cancer Journal • Volume 15, Number 2, March/April 2009 93
of research on HRT over the past decades, we were surprised by the
enormous discrepancy we found between the belief that hormones
are dangerous and the lack of supporting data.
Science is a process; it is rare that a single study gives us a
Yet the news-hungry media crave “break-
throughs” and thrive on scare stories. Thus, it is essential to look
behind the headlines to the actual data, to try to get a sense of the
larger picture that emerges over time and across studies. Sometimes
that larger picture yields a clear image; sometimes, as with HRT, it
becomes foggier than ever. Two statistical errors common to re-
search on HRT have contributed to that fog: one has to do with how
risks are reported; the other has to do with the often inappropriate
“mining” of data, when researchers retrospectively hunt around in
their ﬁndings for something, anything, that might seem to be a
signiﬁcant risk factor.
Consider, ﬁrst, the difference between absolute risk and
relative risk. The media, following the example of many researchers
themselves, tend to report relative risks, which are expressed in
percentages that can seem more important than they are. For exam-
ple, if we tell you that the relative risk of breast cancer is increased
by 300% in women who eat a bagel every morning, that sounds
serious, but it is not informative. You would need to know the
baseline absolute number of new breast-cancer patients. If the
number shifted from 1 in 10,000 women to 3 in 10,000 women, that
is a 300% increase, but it is very likely a random artifact. If the risk
had jumped from 100 to 300 in 10,000, also a 300% increase, we
might reasonably be concerned. In large epidemiological studies that
generally include tens of thousands of people, it is very easy to ﬁnd
a small relationship that may be considered “signiﬁcant” by statis-
tical convention but which, in practical terms, means little or nothing
because of the low absolute numbers.
This is why scientists who are working to promote statistical
literacy, especially in helping the public and physicians understand
actual versus inﬂated risks of diseases and treatments, emphasize
that knowing the baseline of absolute numbers when comparing two
groups is essential.
Two major consensus projects on the reporting
of clinical trials concluded that stating relative risks alone is often
deceptive; results should be provided in absolute numbers, not only
as percentage changes.
A reliance on relative risks can also create misleading, faulty
comparisons. For example, let us say that 3% of the people who eat
chocolates develop cavities, and 2% of people who do not eat
chocolates develop cavities. The absolute difference between these
populations is only 1%. That means that for every 100 people who
eat chocolates, 1 extra person will develop cavities (in addition to
the 2 who will develop cavities without eating a single trufﬂe). This
is not a particularly frightening risk if you enjoy chocolate. But
suppose we report the identical conclusion as a relative risk: 1
additional case divided by the 2 baseline cases gives us an increased
relative risk of 0.5 or 50%. A 50% increased risk in cavities if you
occasionally eat chocolates! Stop at once!
Many of the studies of HRT and risk of disease, especially
breast cancer, have produced statistically modest or borderline
results that have been made to look more impressive than they
actually are by reporting them as relative risks. Consider Table 1,
which lists the reported increases in relative risks associated not only
but also with birth weight,
eating 1 additional serving of French fries per week during pre-
working on a night shift,
working as an airline ﬂight attendant in 2 different airlines,
suffering from severe caloric restriction during the 1944 –1945
and the use of electric blankets
by African-American women.
You can see at a glance how weak
these associations are; to put them in perspective, we included the
results for a real ﬁnding—smoking and lung cancer—at the bottom
of the table.
The relative risks in almost all cases are very low, and
the use of HRT is virtually the lowest, being less risky than eating
ﬁsh or grapefruit, using antibiotics, or being a ﬂight attendant.
Another way of misrepresenting ﬁndings comes from the
practice, severely frowned upon in research, of retrospective sub-
stratiﬁcation, commonly known as “data mining” or “data dredg-
Data mining occurs when researchers, having failed to
ﬁnd the statistically signiﬁcant associations that they had originally
hypothesized would exist between a possible risk factor and a
disease, go back into their data and rummage around, looking for
other factors that might show a statistical link to the dependent
variable in question. This effort might yield interesting questions or
hypotheses for future research, but the problem is that in a data set
of many thousands of people, some relationship that is unearthed
retrospectively will turn out to be statistically signiﬁcant (ie, P⬍
0.05) just by chance.
In Against the Gods: The Remarkable Story of
A consensus article on how best to report ﬁndings from randomized trials cautioned
authors to “especially resist the temptation to perform many subgroup analyses.
Analyses that were prespeciﬁed in the trial protocol are much more reliable than
those suggested by the data.” The authors did not mince words: “The strategy for
reporting study results should be speciﬁed before the results are known, and
selective reporting or emphasis of statistically signiﬁcant results based on ex post
factosubgroup analyses should be discouraged.”
TABLE 1. Risk Factors Associated With the Development of
Interval (CI)* References
0.77 0.59–1.01 34
Birth weight 1.09
Fish intake 1.14 1.03–1.26 36
Premarin/Progestin 1.24 1.01–1.54 37
Premarin/Progestin 1.26 1.00–1.59 25
(1 additional serving
1.27 1.12–1.44 38
Grapefruit 1.3 1.06–1.58 39
Night shift work 1.51 1.36–1.68 40, 41
1.87 1.15–2.23 42, 43
2.01 0.92–4.41 44
2.07 1.48–2.89 45
4.1 1.70–8.50 46
Electric blanket use
4.9 1.50–15.6 47
Tobacco smoking and
26.07 6.58–103.3 48
*A CI provides a range (an interval) with a speciﬁed probability that a given result
will, with continued replications, fall within it 95% of the time (90% or 99% are also
used). In the case of large-scale epidemiological studies, if the spread of the conﬁdence
interval includes the number 1.0, the result is not considered statistically signiﬁcant even
in the presence of a low Pvalue. Generally speaking, the lower limit of the CI should
be at least 3.0 before the ﬁnding is considered a strong, reliable one.
†The odd ﬁnding that the relative risk is lower than the lower limit of the conﬁdence
interval is not a typo. The RR of 1.09 is a calculated increase per 1000 g (2.2 pounds)
of weight at birth.
‡RR was maximum for those exposed to severe famine only between ages 2 and 9.
§1–50 d of antibiotic use ⫽RR 1.45; more than 1001 d of antibiotic use ⫽RR 2.07.
But apparently this result depends on why a woman was taking the antibiotic: There was
no increase in RR for women using tetracycline or macrolide for acne or rosacea.
¶Increased RR most pronounced for more than 10 yr of use, especially when
women who used the device for more than 6 mo per yr were excluded.
Bluming and Tavris The Cancer Journal • Volume 15, Number 2, March/April 2009
© 2009 Lippincott Williams & Wilkins94
Risk, the economist Peter Bernstein put it this way: “If you torture
the data long enough, the numbers will prove anything you want.”
A now-famous example of the spurious results that can
emerge from data mining can be found in an article that was
submitted to the Lancet in 1988, reporting that men hospitalized for
acute heart attacks who had been taking an aspirin daily had a better
survival rate than similarly hospitalized men who had not been on
aspirin. This was clearly an important ﬁnding, and the editors agreed
to accept this article with 1 condition: The authors would have to
retrospectively substratify the 17,187 men in their study according to
a variety of factors, including the men’s age, weight, and race. Now,
it would certainly be good to know whether the beneﬁt of taking
aspirin (or any other drug) is affected by how old you are or whether
you are overweight or Asian, or other possible demographic factors.
But the authors refused to do this reanalysis, explaining that that the
beneﬁt or risk for these subcategories would best be assessed by a
new prospective study. The editors insisted: no substratiﬁcation, no
publication. And so the authors eventually turned in a revised article
with the additional ﬁndings, including a slightly adverse effect of aspirin
on mortality in patients born under the astrological signs of Gemini
or Libra, in contrast to a strikingly beneﬁcial effect of aspirin for
patients born under all other astrological signs. The editors agreed to
publish the article if the astrological results were omitted. “You
wanted retrospective substratiﬁcation, we gave you retrospective
substratiﬁcation,” the authors said (in effect), and demanded that the
Lancet stick to the deal. And so this landmark article was published,
with a new title that began: “Aspirin’s effect on myocardial infarct
mortality and astrology.”
a Nobel Laureate in physics, had a good
test for truth in science. He said: “If something is true, really so, if
you continue observations and improve the effectiveness of the
observations, the effects stand out more obviously. Not less obvi-
ously.” The relationship between cigarette smoking and lung cancer
is an example of the truth becoming clearer with repeated observa-
tions: an association between them is noted, then conﬁrmed with
replications, and further understood when the biologic mechanism
accounting for the association is identiﬁed. In the case of lung
cancer, the epidemiologic data have been consistent across many
studies, revealing a 10- to 30-fold (1000%–3000%) increase in the
risk of lung cancer in smokers compared with nonsmokers. Cigarette
smoke was then shown to cause premalignant changes in the lungs
of laboratory animals; similar changes have been seen in the lungs
of smokers, including those who have developed lung cancer.
The strength and consistency of these data are sufﬁcient to draw a
conclusion about a causal relationship: cigarette smoking causes a
signiﬁcant increase in the risk of lung cancer.
In contrast, the relationship between HRT and breast cancer is
still not clear despite a vast amount of research, study, and reporting
over many decades.
Table 2 reviews the highlights of research
from the ﬁrst manufacture of estrogen tablets (Premarin) in 1942 to
the most recent studies in 2008; as you can see, the list is a jumble
of positive ﬁndings, negative ﬁndings, and meaningless ﬁndings. Let
us see why.
HRT AND BREAST CANCER: IS THERE A LINK?
On July 9, 2002, the National Institutes of Health issued a
press release: “The National Heart, Lung, and Blood Institute of the
NIH has stopped early a major clinical trial 关the Women’s Health
Initiative兴of the risk and beneﬁts of combined estrogen and pro-
gestin in healthy menopausal women due to an increased risk of
invasive breast cancer.” The WHI investigators reported that
women who had been randomly assigned to take a combination of
estrogen and progestin had a small increased relative risk of
breast cancer (relative risk ⫽1.26) when compared with women
who were randomly assigned to a placebo.
(1.26 means a 26%
increase in risk.)
What few noticed in the published article was this little
sentence: “The 26% increase in breast cancer incidence among the
HRT group compared with the placebo group almost reached nom-
inal statistical signiﬁcance.” “Almost” means it did not reach statis-
tical signiﬁcance. Of course, any increase might be of legitimate
concern, warranting further investigation. But were this ﬁnding
valid, one would have expected to see an even greater increased
incidence of early, noninvasive breast cancer, the kind that precedes
invasive breast cancer. There was, however, no difference between
the 2 groups in the incidence of this early breast cancer, nor in deaths
from breast cancer.
Yet many reporters and physicians treated that 26% increase
in relative risk as being not only statistically signiﬁcant but also
medically signiﬁcant. In an editorial published in the June 25, 2003,
issue of JAMA, Peter Gann and Monica Morrow
statistically signiﬁcant 26% increase in breast cancer incidence
contributed to the overall negative effect of estrogen plus progestin.”
Editorials like this are generally what gets read and quoted in the
press and by many physicians.
investigator and biostatistician for the WHI Clinical Coordinating
Center, claimed the study had demonstrated that “breast cancer rates
were markedly increased among women assigned to the estrogen
plus progestin group.” Markedly? Even if this ﬁnding had been
signiﬁcant, which it was not, it would have meant that HRT
increased the risk from 5 women in 100 to 6 in 100.
there is research showing that women diagnosed with breast cancer
while taking HRT have been reported to have a better prognosis,
regardless of what stage their cancer was in, than women diagnosed
in the absence of HRT.
In 2003, the WHI published a follow-up in which they
asserted that their 2002 report “conﬁrmed that combined estrogen
plus progestin use increases the risk of invasive breast cancer.” Their
assessment this time was that HRT “signiﬁcantly increased the
incidence of breast cancer within a ﬁve-year period.” The relative
risk, 1.24, was actually a bit lower than the 2002 ﬁnding of 1.26, and
it barely achieved statistical signiﬁcance.
In 2006, in another update of this same cohort of patients, the
WHI reported no increased risk of breast cancer among women
randomized to combined estrogen-progestin treatment. The “signif-
icant” relative risk had completely vanished.
This news did not
One of the studies that is still frequently cited by those
striving to ﬁnd an association between HRT and breast cancer is a
1989 Swedish study (Table 2), which reported a 440% increased risk
of breast cancer among women taking combined estrogen and
progestin for more than 6 years.
This sounds impressive, until we
learn that it was not statistically signiﬁcant (the conﬁdence interval
was 0.9 –22.4) and that it was based upon only 10 patients in the
study who developed breast cancer while taking HRT. The baseline
study population consisted of the 23,244 women in Uppsala, Swe-
Remarkably, another article in that same issue of JAMA cited the same 2002
article correctly: “After 5.2 years of follow-up the WHI reported that com-
bined HRT was associated with a statistically nonsigniﬁcant 26% increase in
We calculate this increase based on data from a 2007 publication from the
National Center for Health Statistics, showing that the average risk of breast
cancer across 3 age groups (40 –59, 60– 69, 70, and older) is 4.82%, about 5
in 100. Even if the WHI ﬁnding of a 1.26 increased relative risk because of
hormones had been statistically signiﬁcant, then the risk will increase from
5% to an additional 26% of the 5%. This increase in incidence is obtained by
multiplying the baseline, 4.82% average risk, by 1.26, which yields a revised
risk of just under 6%, or 6 in 100. (In absolute numbers, from 182,500 cases
to 184,325 cases.)
The Cancer Journal • Volume 15, Number 2, March/April 2009 HRT
© 2009 Lippincott Williams & Wilkins 95
den, who received prescriptions for HRT in a 3-year period. The
researchers took a much smaller subset of that population to analyze,
calculated that 2.2 women would be expected to get breast cancer,
and found that 10 actually did— hence the “440% increased risk.”
In addition, the Swedish study found no statistically signiﬁ-
cant increased risk of breast cancer among women who used
estrogen alone, which might make us wonder why estrogen was seen
as the villain. Elizabeth L. Barrett-Connor,
in an editorial accom-
panying the report, concluded: “For the average North American
woman, who will be postmenopausal for one third of her life, the
beneﬁts of estrogen seem strongly established. In my opinion, the
data are not conclusive enough to warrant any immediate change in
TABLE 2. HRT and Breast Cancer: A Timeline of Relevant Events and Studies
1942: Researchers develop methods to extract large quantities of estrogen from the urine of pregnant mares, and Ayerst Laboratories launches Premarin
(from PREgnant MARes’ urINe), the ﬁrst estrogen tablets.
1950s: Ayerst Laboratories begins a marketing campaign promoting the use of Premarin to lessen menopausal symptoms.
1966: New York gynecologist Robert Wilson publishes Feminine Forever, a best seller that promises youth, beauty, and a “full sex life” for menopausal
women through the use of hormone therapy.
1975: Postmenopausal women on estrogen are found to have a 4- to 8-fold increase in the risk of uterine cancer.
Mid 1980s: The addition of progestin to estrogen negates the increased risk of uterine cancer associated with estrogen alone.
By 1986, over 20 million
prescriptions for non-contraceptive hormones are dispensed.
1982: A study ﬁnds that estrogen is not associated with an increased risk of breast cancer.
1974–1989: Of the 26 most cited reports during this period that have investigated the association between HRT or ERT and breast cancer
5 report an increased risk
7 report a decreased risk
14 report no signiﬁcant association.
1984: A study reports that estrogen does not increase the risk of breast cancer, even when taken for many years.
1989: A Swedish study reports a 440% increased risk of breast cancer associated with the administration of combined estrogen and progestin for more
than 6 yr. However, this risk is based upon only 10 patients in the study who developed breast cancer while taking HRT.
1989: A 17-yr follow-up study of more than 3000 women who had had benign breast lesions and were taking estrogen ﬁnds the women had no increased
risk of developing breast cancer. In fact, estrogen slightly lowered the breast cancer risk in women with atypical hyperplasia and several other
1992: The ﬁrst prospective, randomized, controlled study of combination HRT and breast cancer risk is published. It ﬁnds that even after 22 yr of use,
women on HRT do not have an increased incidence of breast cancer.
1995: A study reports no increased risk of breast cancer in postmenopausal women on HRT, even after more than 15 yr of use.
1995: The Nurses’ Health Study, an observational study that followed 121,700 female registered nurses from 1976 through 1992, ﬁnds no increased risk
of breast cancer when women who had ever used HRT are compared to women who never took HRT, and no increased risk of breast cancer even
when HRT users for over 10 yr are compared to never users.
1996: A study reports that ever-use of estrogen replacement therapy is associated with a slightly decreased risk of fatal breast cancer.
1997: A prospective cohort study of nearly 42,000 Iowan women with a family history of breast cancer reports that HRT use is not associated with a
signiﬁcantly increased risk of breast cancer, but is associated with a signiﬁcantly reduced mortality rate from all causes.
2000: A study reports a 40% increased risk of breast cancer associated with HRT.
However, this risk is limited to women weighing no more than 90
2000: A retrospective study ﬁnds an increased risk of breast cancer among estrogen-only users, but only after 15 yr of use. A barely signiﬁcant increased
risk of breast cancer among combination estrogen-progestin users is found after 5 yr.
2002: The Women’s Health Initiative (WHI) terminates the estrogen-progestin arm of their study prematurely because they claim to have found an
increased risk of breast cancer. This increased risk is, however, not statistically signiﬁcant.
2003: The WHI “conﬁrms” its 2002 ﬁnding, reporting a small increased risk of breast cancer among women on HRT. Analysis of the data according to
kind of cancer ﬁnds either no statistical signiﬁcance or barely a 1% increased risk.
2003: A British study, published in The Lancet, entitled “The Million Women Study,” reports an increased risk of breast cancer in women taking ERT or
HRT. However, they also ﬁnd:
●No increase in risk of breast cancer in past users of either estrogen or estrogen-progestin, regardless of duration of use.
●The increased risk of breast cancer is found only in current users.
●The average period of follow-up is only 2.6 yr.
2004: The WHI reports no increased risk of breast cancer associated with the use of estrogen alone.
2006: The WHI reafﬁrms its 2004 ﬁnding of no increased risk of breast cancer among women taking estrogen, even after 7 yr. This time, they report that
women who had used HRT in the past had a lower rate of breast cancer than women who had never taken hormones.
2006: A study of 9000 Japanese women ﬁnds that HRT users are less likely to develop breast cancer than never-users.
2006: A study reports no increase in breast cancer incidence among women who have been taking estrogen, even after 8 or more years.
2006: The WHI now reports no increased risk of breast cancer even among women randomized to take combined estrogen and progestin.
2008: The WHI reports that the risk of cardiovascular events, malignancies, breast cancers, and deaths from all causes was higher in the HRT group than
in the placebo group even 3 yr after the women stopped taking HRT. However, none of the associations between HRT and breast cancer or mortality
rates is statistically signiﬁcant.
2008: An observational study of 472 postmenopausal women who have a genetic predisposition to breast cancer, the BRCA1 mutation, ﬁnds that hormone
use, either as HRT or ERT, is not associated with increased risk of breast cancer. On the contrary, it is associated with a decreased risk.
Bluming and Tavris The Cancer Journal • Volume 15, Number 2, March/April 2009
© 2009 Lippincott Williams & Wilkins96
the way we approach hormone replacement.” The Harvard Medical
School Health Letter reviewed the Swedish study and concluded:
“The most striking ‘result’ was in women who took estrogen
combined with progestin for more than 6 years, and this was what
made headlines. These women seemed to have 4.4 times the average
risk of developing breast cancer. But there is a very important reason
not to take this ﬁgure literally. There were only 10 women in this
group, too few to provide a statistically stable result, the true value
had a 95% chance of being 10% below the average or as high as 22.4
times the average (an incredible ﬁgure), or somewhere in between.
Earlier research has given us no reason to expect a strong association
between estrogen replacement and breast cancer.”
Yet in today’s
climate, that very same study is used to support the argument that
HRT causes breast cancer.
To further their case, some investigators have turned to
retrospective analysis. Several of the “signiﬁcant” associations in
Table 1 were a result of data mining: the use of antibiotics increases
relative risk, but not among women using tetracycline or macrolide
for acne or rosacea
(apparently breast cancer needs to know why
a woman is taking an antibiotic); the increased risk of surviving the
Dutch famine occurs only among women who were between 2 and
9 at the time
; and, in the most unintentionally funny result, the
breast cancer risk associated with using electric blankets increased
among African American women who used the blankets for more
than 10 years— but only if those who used them for more than 6
months per year were excluded from analysis.
Table 2 includes
some good examples of data mining too, such as a 2000 study that
found a 40% increased risk of breast cancer associated with HRT. It
took some determination to get that result, because the increased risk
applied only to women weighing not more than 90 pounds.
The WHI and the observational (nonrandomized) Nurses’
Health Study, which followed 121,700 female registered nurses
from 1976 through 1992, are both guilty of data mining. When the
association between HRT and breast cancer repeatedly failed to
reach statistical signiﬁcance, the investigators did not say, “Good
news! Looks like HRT is pretty safe, at least on the breast cancer
question.” Rather, they jumped back into the data pool, trying to ﬁnd
something that was signiﬁcant—maybe that some form of HRT is
harmful for some women, or is related to some kinds of breast
cancer, or is hazardous after some length of time. These are all
serious possibilities, of course, and might warrant a new prospective
study. But we repeat: when you get results from retrospective
analysis, rather than as a premeditated focus of investigation under
controlled conditions, the ﬁndings are likely to be confusing, unrep-
licated in subsequent studies, and biologically improbable—like the
spurious link between aspirin and astrological sign. And that is the
picture we get of the relationship between HRT and breast cancer.
Thus, when the Nurses’ Health Study found no increased risk
of breast cancer among women on HRT, they then compared women
who had ever used HRT in the past with women who never had
taken it. They found no increased risk of breast cancer even among
women who had taken HRT for over 10 years, compared with never
users. So they then further substratiﬁed their sample into (a) current
users of HRT and (b) women who had used HRT in the past and had
stopped. This time the investigators found an increased risk of breast
cancer, but only among women who were currently on HRT or ERT
and had been for at least 5 years.
How can you get an increased
risk among a group of women who have taken hormones for 5 years
but not for more than 10 years? That is what data mining gives you.
In contrast, here is what you learn if you initially set out to
study a question involving a subset of women at risk for breast
cancer. If HRT were a signiﬁcant risk factor, then it should surely
pose particular risks for women who have a BRCA1 or BRCA2
genetic mutation, which predisposes them to develop the disease.
When these women have their ovaries removed, their risk of devel-
oping breast cancer falls by half. But the surgery induces meno-
pause, and some patients subsequently take HRT to alleviate meno-
pausal symptoms. Are they in special danger? Does taking estrogen
negate the beneﬁt of the surgery?
To ﬁnd out, researchers compared the use of HRT and ERT
in 236 breast cancer patients and 236 matched controls, all of whom
carried a mutation in BRCA1. (There were not enough women with
BRCA2 to be included.) The results, reported in the October 1, 2008
issue of the Journal of the National Cancer Institute, found no
increased risk among women taking hormones, whether they had
undergone natural, age-related menopause, or surgically induced
This ﬁnding is so important, and so counter-intuitive,
that we want to underscore its message. If lowered estrogen levels
following removal of the ovaries were the reason for the drop in
breast cancer risk in women with the BRCA1 mutation, then it is
irrational to give them supplementary estrogen to alleviate symp-
toms, right? Yet, according to another large-scale study and its own
follow-up, administering estrogen to women with BRCA1 muta-
tions, following removal of the women’s ovaries, did not nullify the
beneﬁts of the surgery. Their risk of breast cancer remained just as
Moreover, the majority of observational studies have found
no increased risk of breast cancer associated with HRT,
ing studies in which HRT was given to women with a family history
of breast cancer.
Many researchers today are inclined to dismiss
observational study conclusions, even though the Nurses’ Health
Study is among them. What is wanted, they say, is a prospective,
randomized study, the gold standard for determining the validity of
ﬁndings in clinical trials. Yet a review of the medical literature,
comparing results from observational studies and from randomized
controlled trials, found that both methods usually produce similar
Another review found that the persistent validity of
conclusions 20 years after initial publication was 87% among
nonrandomized (observational) trials and 85% among randomized
One reason is that randomized controlled trials are
like the 10 Commandments—a ﬁne ideal, but very difﬁcult to
execute in practice. For starters, most participants know if they are
taking an active medication or an inert placebo, which affects their
subsequent behavior; true randomization and double-blinding are
often difﬁcult, if not impossible, to achieve.
We are not saying
that observational studies are “as good” as the gold standard, but
rather that both methods have strengths and weaknesses, and that,
again, it is important to consider the overall pattern of evidence
rather than any single study.
Some investigators who believe that the relative risks of HRT
are serious enough to warrant concern acknowledge that the absolute
risks from this treatment are small. In one worst-case analysis,
researchers calculated that a 50-year-old woman taking estrogen and
progestin for 10 years has only a 4% risk of breast cancer. Without
HRT, her risk would be 2%.
(An alarmist headline writer might
report this ﬁnding by stating that a woman’s risk is “doubled” if she
takes HRT for 10 years, whereas a reassuring statistician would say
that she has a 96% chance of remaining free of breast cancer versus
98% if she does not.) Moreover, even if HRT increases the risk of
breast cancer by this modest increment, research suggests that
women on HRT live longer than those not taking HRT, and that
HRT-treated women have a lower death rate from breast can-
How can the very hormones that allegedly increase the
When one of us (AB) directly asked the investigators in print why they had
retrospectively subdivided their sample into current and past users, they did
not answer then or since.
The Cancer Journal • Volume 15, Number 2, March/April 2009 HRT
© 2009 Lippincott Williams & Wilkins 97
risk of breast cancer also be responsible for a better survival rate
from that cancer?
BUT DOES ESTROGEN CAUSE CANCER?
The hypothesis that hormones are linked to breast cancer was
originally derived from 2 well-documented facts: the incidence of
breast cancer is 100 times greater in women than in men, and the
earlier a woman’s menarche and the later her menopause, the greater
her risk of breast cancer.
These observations suggested, reason-
ably, that perhaps having more years of circulating estrogen was the
culprit. As we noted in the example of cigarette smoking and lung
cancer, the ﬁrst step in the scientiﬁc process is to document a reliable
association, and the second step is to demonstrate the biologic
mechanism that might account for it. In the case of the hypothesis
that estrogen causes breast cancer, not only has the association
turned out to be weak or nonexistent, but also the second step has
been contradicted by various lines of evidence:
YBirth control pills, which used to contain far more estrogen than
HRT does, should therefore increase the risk of breast cancer.
Although controversy continues on this question,
lished studies ﬁnd that oral contraceptives do not increase the
YWomen taking estrogen alone (ERT) should have a higher risk
of breast cancer. They do not. The WHI itself found that they
have no increased risk, even after an average follow-up of 6.8
years; if anything, these women have a slight decrease in
YThe incidence of breast cancer increases as women grow older.
If taking estrogen is part of the reason, the breast cancer rate
among postmenopausal women who do not take HRT should
decrease with age, along with their naturally declining estrogen
levels. It does not.
YAccording to the National Cancer Institute’s Division of Can-
cer Etiology, estrogens are not direct carcinogens for mammary
Estrogen can, however, induce cell proliferation. So
the WHI modiﬁed their original hypothesis into this version:
mutation-inducing agents are all around us, and the higher the
rate of cell proliferation, the more possible it is that a prolif-
erating cell will be exposed to a mutagen and become malig-
nant. The problem with this argument is that the endometrium,
the lining of the uterus, is more sensitive to the proliferative
effect of estrogen than is the breast. As we mentioned, women
who take estrogen alone have a 5– to 6-fold increased risk of
uterine cancer, but no increased risk of breast cancer. If pro-
longed stimulation of estrogen solely from an early menarche
and a late menopause predisposed women to cancer, we would
see its effects on rates of endometrial cancer. We do not.
Mammary gland cells are divided into those that have an estrogen
receptor (ER) molecule on their surface, ER positive, and those that
do not have this estrogen receptor, ER negative. Some researchers
hypothesize that HRT might cause an increase in breast cancer by
stimulating the estrogen-receptor-positive cells. The problem with
this seemingly logical notion is that ER positive cells are, most
often, not the ones proliferating in breast cancer. The really danger-
ous cells are the 5% that constitute the cancer stem cell, and they are
not ER positive. ER expressing cells of the mammary epithelium are
distinct from the stem cell population, and any effect of estrogen on
the stem cells is mediated indirectly.
But what about drugs like tamoxifen, an “estrogen antago-
nist,” which are given to breast-cancer patients to reduce the chance
of recurrence? One of the arguments that estrogen causes or pro-
motes breast cancer is that tamoxifen helps to reduce or retard the
growth of ER positive breast cancer by competitively blocking the
binding of estrogen to the estrogen receptor on breast cancer cells.
However, several lines of research dispute this belief. For one thing,
when tamoxifen is given to premenopausal women, their natural estro-
gen levels increase up to 5-fold.
This rise in estrogen should block
any competitive binding of tamoxifen, yet tamoxifen’s effect against
breast cancer works as well in these premenopausal as in postmeno-
Second, approximately 40% of ER positive pa-
tients fail to respond to tamoxifen.
Third, laboratory studies have
shown that tamoxifen inhibits the stimulatory effects of growth factors
involved in breast cancer
even in the absence of estrogen.
addition, after treatment with tamoxifen, some breast cancer cells
actually acquire the ability to proliferate
—and low doses of estrogen
have been shown capable of killing them.
Finally, tamoxifen has
also been shown to have a therapeutic effect on ER negative breast
cancer cells, both in laboratory studies and in human patients.
In other words, tamoxifen works in a variety of ways that are
exclusive of its action on estrogen receptors. Because the precise
mechanisms responsible for its therapeutic effect remain un-
it seems inadequate and simplistic to claim that the
success of tamoxifen supports the view that estrogen causes breast
cancer or stimulates cellular proliferation in breast cancer. The
overall picture to date, therefore, persuades us that HRT is not a
major risk factor for breast cancer.
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE
Heart-disease deaths exceed breast cancer deaths in every
decade of a woman’s life including her 30s, and as women age, their
risk of death from heart disease is more than 5 times as great as that
from breast cancer.
Understanding the role of HRT in the possible
development or progression of heart disease, or protection against it,
is therefore crucial.
Throughout the 1980s, many studies found a cardiovascular
beneﬁt of taking HRT. A 1989 review of 19 published studies of
ERT’s effect on heart disease reported that ERT was associated with
at least a 30% reduction in clinical coronary artery disease. This
conclusion was consistent among 90% of the cohort studies, 63% of
the case control studies, and the only double-blind randomized trial
that had been done to date.
By 1991, a New England Journal of
Medicine editorial reported that a consensus of epidemiological
studies had shown that women who are given postmenopausal
estrogen have a 40% to 50% reduction in the risk of coronary artery
disease in comparison with women who do not receive such thera-
In 2000, the Nurses’ Health Study reported that HRT reduced
the development of primary cardiovascular disease by nearly
a condition responsible for more than 300,000 deaths
among US women per year.
Subsequently, a large randomized study, the Heart and Estro-
gen/Progestin Replacement Study, found a statistically signiﬁcant
increase in heart events in women with known coronary artery
disease receiving HRT— but only during the ﬁrst year of use.
2002, the WHI reported that women on HRT, but not women on
estrogen only, had a slightly increased relative risk of “heart
events”— coronary heart disease (including acute myocardial infarc-
tion requiring hospitalization or silent myocardial infarction), death
because of heart disease, angina, or indications for revascularization
But, as in the Heart and Estrogen/Progestin Replacement
Study, this increased risk occurred only among women in the ﬁrst
year of taking combined HRT.
In 2007, the WHI investigators
Technically, they also found a signiﬁcant increase in cardiovascular events
among women in their ﬁfth year of taking hormones, but that seems to be a
result of a ﬂuke—a surprisingly low incidence of coronary heart disease in the
comparison placebo group.
Bluming and Tavris The Cancer Journal • Volume 15, Number 2, March/April 2009
© 2009 Lippincott Williams & Wilkins98
revised their 2002 ﬁndings, now concluding that women who start
HRT within the ﬁrst 10 years following menopause actually reduce
their risk of coronary artery disease, whereas those who start after
that period slightly increase their risk.
In another conﬂuence of a
randomized trial and an observational study, the Nurses’ Health
Study reached the same conclusions.
Why should HRT increase cardiovascular risk only in the ﬁrst
year, and only among older women? We know from primate data
that continuous estrogen keeps blood vessels healthy; we also know
that estrogen replacement after a hormone-free interval cannot
reverse vascular damage.
The Estrogen Prevention of Atheroscle-
rosis Trial and Estrogen Replacement and Atherosclerosis studies
are consistent with the animal data.
One leading explanation is
that among women who do not have heart disease, HRT reduces
oxidation of low-density lipoproteins and causes blood vessels to
dilate, thereby inhibiting the development of atherosclerosis. How-
ever, in women who do have underlying heart disease, HRT can be
potentially harmful, because it can induce inﬂammation in existing
arterial plaque, causing a stable plaque to rupture, and can also
promote bleeding into the plaque, both of which can lead to
blockage of a critical coronary artery.
This analysis would explain why studies that have enrolled
women of a younger age, like the Nurses’ Study, found that HRT
had a protective effect: these women were less likely to have arterial
plaques. But in the WHI, only 10% of the women were between 50
and 54 years old, ages at which HRT might have played a beneﬁcial
role; 70% were 60 to 79 years old, in an age range where we would
expect to ﬁnd previously formed plaques.
Although HRT was
effective in reducing LDL, total cholesterol, and glucose, and in
raising high-density lipoprotein levels, these beneﬁts did not result
in a reduced incidence of cardiovascular disease in the older women,
consistent with preexisting atherosclerotic disease in this population.
Atherosclerosis was probably present in the WHI population be-
cause, in addition to the median age of 63, fully 70% of the women
were overweight and half of them were obese. Nearly 50% were
either current or past cigarette smokers and more than 35% had been
treated for high blood pressure.
Yet women with these well-
established risk factors for cardiovascular disease were not excluded
from the analysis of HRT and cardiovascular events. The WHI
investigators have repeatedly stated that all of the women they
recruited were healthy, a prerequisite for participation in this pri-
mary-prevention study; these assertions are difﬁcult to reconcile
with the actual medical histories of so many of the women.
Our conclusions are:
YHRT may have beneﬁcial effects on the heart for women who
start taking hormones early in menopause (around age 50)
because estrogen promotes healthy blood vessels and may help
delay the formation of plaque.
YHRT probably has no protective effect on women who begin
the use of HRT later, in their mid-60s.
YHRT is potentially risky for women who begin taking it in their
60s, at least for the ﬁrst year, especially if they have preexisting
Overall, we share the conclusion of most cardiologists: there is no
reason for women to take hormones primarily to help forestall or
prevent cardiovascular disease, given that there are other effective
ways of reducing heart-disease risk.
Before moving on, let us consider one other headline-grab-
bing, fear-inducing story from the WHI. In 2004, the WHI an-
nounced it was stopping the estrogen-only arm of the study because
the use of estrogen increased the risk of nonfatal stroke by 12 per
10,000 women per year.
However, the WHI investigators had an
extremely broad deﬁnition of “stroke”—including transient, “subtle
neurologic deﬁcits” that resolved in a day or two. Some epidemiol-
ogists have argued that this small apparent increase was artiﬁcially
introduced by a “detection bias”: the fact that women on HRT,
having been made so sensitive to possible adverse effects of hor-
mones, had become hyperalert to any symptoms. Indeed, when these
critics reanalyzed the ﬁndings, controlling for detection bias, the
increased risk of stroke vanished.
COGNITIVE FUNCTIONING AND ALZHEIMER’S
Laboratory studies with animals have suggested that estrogen
can modify the structure of nerve cells in the brain and alter the way
they communicate with each other, a process called neuroplasticity.
The real-life applications of this research remain uncertain and
controversial, but some evidence indicates that estrogen therapy
administered after menopause may prevent, or at least delay, the
onset of Alzheimer’s disease.
The WHI researchers, however, remain unconvinced of this
possibility. In their 2003 report, the WHI authors concluded that
estrogen plus progestin increased the risk for dementia in women
aged 65 and older, and did not prevent the development of mild
cognitive impairment—further support, they said, for their conclu-
sion that the risks of HRT outweighed any possible beneﬁts.
increased incidence of dementia in the HRT group, compared with
women on placebo, occurred as early as 12 months after the women
started HRT. In contrast, there was no increased incidence of mild
cognitive impairment between the 2 groups during the entire trial
period. If HRT were really harmful to the brain, surely mild
cognitive problems would emerge before full-blown dementia.
In 2004, a follow-up WHI article repeated the assertion that
estrogen increased the risk for both dementia and mild cognitive
However, when women who had mild cognitive
impairment at the start of the study were excluded from analysis, the
results were no longer statistically signiﬁcant.
Yes, we had to read
that twice also. Estrogen is associated with cognitive impairments—
but only among women who are already cognitively impaired.
BENEFITS VERSUS RISKS OF HRT
It is difﬁcult to resist the conclusion that the WHI investiga-
tors have been doing everything they could to wring the bleakest
possible interpretation from their recalcitrant data. They do not even
acknowledge the single greatest beneﬁt of HRT: its relief of meno-
pausal symptoms. On the contrary, they have concluded that “in
postmenopausal women, estrogen plus progestin did not have a
clinically meaningful effect on health related quality of life,” even
after taking HRT for 3 years.
Because it takes less than a week for
most symptomatic menopausal women to feel better after starting
HRT, many readers of the WHI article may be forgiven for asking:
what were these investigators thinking?
To be sure, the WHI was not interested in the effect of
hormones on menopausal symptoms; they were investigating the big
problems— breast cancer, heart disease, and cognitive impairment.
That is a legitimate goal, of course, but then why publish an article
on the menopausal symptoms they did not study? The article notes
that women who reported moderate or severe menopausal symptoms
“were discouraged from participating in the study” and, perhaps as
a result, “Moderate or severe vasomotor symptoms at baseline were
present in only 12.7% of study patients.” Not surprisingly, among
those 12.7% with distressing symptoms, those randomized to take
hormones reported signiﬁcant relief compared with the women on
placebo. The women who never had symptoms reported no relief of
We have no way of knowing why the investigators associated
with the WHI have been so determined and persistent in claiming
The Cancer Journal • Volume 15, Number 2, March/April 2009 HRT
© 2009 Lippincott Williams & Wilkins 99
that HRT is dangerous for most women, increasing the risks of
breast cancer, heart disease, stroke, dementia, and cognitive impair-
ment, while not even alleviating menopausal symptoms. These
allegations run contrary to their own published data. In 2007, when
it was reported that breast cancer rates in 2003 had declined, some
investigators attributed it to the fall in HRT use following the 2002
Yet overall rates of breast cancer began to drop
in 1999, and a decreasing death rate from breast cancer can be traced
back to 1990, long before the initial publication of the WHI
Although we do not yet know all the complex factors
required for a malignant cell to develop into a clinically detectable
breast cancer, we know it takes more than 6 months— estimates
range from 2 to 26 years, with an average of about 8 years.
is difﬁcult to understand how a decrease in HRT use would be
reﬂected in a decrease in breast cancer rates within a year.
Finally, if the reported decreased incidence of breast cancer were
due to a decrease in stimulation of subclinical (estrogen–induced
or estrogen–stimulated) tumors, as proposed by the investigators,
the decreased incidence should be conﬁned to small early breast
cancers. It is not.
What does all of this mean for women’s health? Concerns
about HRT are valid, but HRT is not the clear and present danger
that the WHI and much of the media have made it out to be. If
women are going to stop taking HRT solely to avoid breast cancer,
then, on the basis of the studies to date, they should also stop eating
ﬁsh, consuming grapefruit, taking antibiotics, using electric blan-
kets, or serving as ﬂight attendants on Scandinavian airlines—all of
which have been reported to have stronger associations with breast
cancer than does HRT. On the other hand, cardiovascular concerns
may be warranted, although largely among women who are at an
elevated risk of heart disease or who begin HRT in their mid-60s.
The WHI concludes that the risks of HRT far outweigh the
beneﬁts, and even tried to hold HRT responsible for “increased
deaths from all causes” in their 2008 report. None of these associ-
ations were statistically signiﬁcant.
Other investigators, though,
feel just as strongly that the potential health beneﬁts of postmeno-
pausal estrogen replacement, as measured by decreased morbidity
and increased life expectancy— by nearly 4 years, in 1 assessment—
far exceed the risks.
Even the WHI conﬁrmed previously pub-
lished reports of decreased risks of osteoporotic fractures and colon
cancer for women on HRT.
For us, the weight of the evidence is clear: women in
menopause who have symptoms that seriously affect the quality of
their lives should feel secure in taking HRT at the start of meno-
pause and for as many years after as they must to control those
symptoms. Any woman worried about her health and longevity
should quit smoking before she quits hormones, and have screening
mammograms and colonoscopies while she is at it. Years ago, Allen
then editor-in-chief of the American Academy of
Science’s popular magazine, Science 80, described the challenge
their journal faced: “Conveying the way science really works—the
interplay of persistence and luck, the painstaking accumulation of
evidence, the clash of proponent and critic, the gradual dawning of
conviction— demands a look behind the headlines.” In an era when
alarmist headlines get everyone’s attention, it is all the more impor-
tant to read the ﬁne print. Sometimes there is even good news there.
This article was written at the suggestion of the American
Council of Science and Health, whose panel of reviewers provided
many helpful suggestions.
1. Weiss NS. Editorial: risks and beneﬁts of estrogen use. N Engl J Med.
2. Gambrell RD Jr. Use of progestogen therapy. Am J Obstet Gynecol.
3. Cauley JA, Cummings SR, Black DM, et al. Prevalence and determinants of
estrogen replacement therapy in elderly women. Am J Obstet Gynecol.
4. Harris RB, Laws A, Reddy VM, et al. Are women using postmenopausal
estrogens? A community survey. Am J Public Health. 1990;80:1266 –1268.
5. Brett KM, Madans JH. Use of Postmenopausal hormone replacement ther-
apy: estimates from a nationally representative cohort study. Am J Epide-
miol. 1997;145:536 –545.
6. Keating NL, Cleary PD, Rossi AS, et al. Use of hormone replacement
therapy by postmenopausal women in the United States. Ann Intern Med.
7. Castelo-Branco C, Figueras F, Sanjuan A, et al. Long-term compliance with
estrogen replacement therapy in surgical postmenopausal women: beneﬁts to
bone and analysis of factors associated with discontinuation. Menopause.
8. Ettinger B, Pressman A. Continuation of postmenopausal hormone replace-
ment therapy in a large health maintenance organization: transdermal matrix
patch versus oral estrogen therapy. Am J Manag Care. 1999;5:779 –785.
9. Pilon D, Castilloux A-M, Lelorier J. Estrogen replacement therapy: deter-
minants of persistence with treatment. Obstet Gynecol. 2001;97:97–100.
10. Greendale G, Reboussin B, Hogan P, et al. Symptom relief and side effects
of postmenopausal hormones: results from the Postmenopausal Estrogen/
Progestin Interventions Trial. Obstet Gynecol. 1998;92:982–988.
11. Utian WH, Shoupe D, Bachman G, et al. Relief of vasomotor symptoms and
vaginal atrophy with lower doses of conjugated equine estrogens and
medroxyprogestin acetate. Fertil Steril. 2001;75:1065–1079.
12. Barnabei V, Grady D, Stovall D, et al. Menopausal symptoms in older
women and the effects of treatment with hormone therapy. Obstet Gynecol.
13. MacLennan A, Lester A, Moore V. Oral Oestrogen Replacement Therapy
Versus Placebo for Hot Flushes.关Cochrane Review on CD-ROM兴. Oxford,
England: Cochrane Library, Update Software; 2002.
14. NIH State-of-the Science Panel. National Institutes of Health State-of-the
Science Conference Statement: management of menopause-related symp-
toms. Ann Intern Med. 2005;142:1003–1013.
15. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symp-
toms of menopause with black cohosh, multibotanicals, soy, hormone
therapy, or placebo. Ann Intern Med. 2006;145:869 – 879.
16. Heikkinen J, Vaheri R, Timonen U. A 10-year follow-up of postmenopausal
women on long-term continuous combined hormone replacement therapy:
update of safety and quality-of-life ﬁndings. J British Menopause Soc.
17. Lobo RA, Belisle S, Creasman WT, et al. Should symptomatic menopausal
women be offered hormone therapy? Med Gen Med. 2006;8:40 –56.
18. Welton AJ, Vickers MR, Kim J, et al. for the WISDOM team. Health related
quality of life after combined hormone replacement therapy: randomised
controlled trial. BMJ. 2008;337:1190.
19. Weiss NS, Ure CL, Ballard JH, et al. Decreased risk of fractures of the hip
and lower forearm with postmenopausal use of estrogen. N Engl J Med.
20. Consensus Development Conference: Prophylaxis and treatment of osteo-
porosis. BMJ 1987;295:914 –915.
21. Kiel DP, Felson DT, Anderson JJ, et al. Hip fracture and the use of estrogens
in postmenopausal women: the Framingham Study. N Engl J Med. 1987;
22. Grady D, Rubin S, Petitti DB, et al. Hormone therapy to prevent disease and
prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016 –
23. Belchetz PE. Hormonal treatment of postmenopausal women. N Engl J Med.
24. Cauley JA, Seeley DG, Ensrud K, et al. Estrogen replacement therapy and
fractures in older women. Study of Osteoporotic Fractures Research Group.
Ann Intern Med. 1995;122:9 –16.
25. Rossouw JE, Anderson GL, Prentice RL, et al. Writing Group for the
Women’s Health Initiative investigators. Risks and beneﬁts of estrogen plus
progestin in healthy post menopausal women: principal results from the
Women’s Health Initiative Randomized Controlled Trial. JAMA. 2002;288:
26. Nachtigall MJ, Smilen SW, Nachtigall RD, et al. Incidence of breast cancer
in a 22-year study of women receiving estrogen-progestin replacement
therapy. Obstet Gynecol. 1992;80:827– 830.
27. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal
hormones: annual trends and response to recent evidence. JAMA. 2004;291:
Bluming and Tavris The Cancer Journal • Volume 15, Number 2, March/April 2009
© 2009 Lippincott Williams & Wilkins100
28. Ludwig FC. Pathology in historical perspective. Pharos Alpha Omega Alpha
Honor Med Soc. 1993;56:5–11.
29. Taubes G. Epidemiology faces its limits. The search for subtle links between
diet, lifestyle, or environmental factors and disease is an unending source of
fear, but often yields little certainty. Science. 1995;269:164 –169.
30. Gigerenzer G, Gaissmaier W, Kurz-Milcke E, et al. Helping doctors and
patients make sense of health statistics. Psychol Sci Public Interest. 2008;
31. The Asilomar Working Group on Recommendations for Reporting of
Clinical Trials in the Biomedical Literature. Checklist of information for
inclusion in reports of clinical trials. Ann Intern Med. 1996;124:741–743.
32. Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement
for reporting randomized trials: explanation and elaboration. Ann Intern
Med. 2001;134:663– 694.
33. Moher D, Schultz KF, Altman D; for the CONSORT Group. The CONSORT
statement: revised recommendations for improving the quality of reports of
parallel-group randomized trials. JAMA. 2001;285:1987–1991.
34. Chlebowski RT, Hendrix SL, Langer RD, et al; for the WHI Investigators.
Inﬂuence of estrogen plus progestin on breast cancer and mammography in
healthy postmenopausal women: the Women’s Health Initiative Random-
ized Trial. JAMA. 2003;289:3243–3253.
35. The Women’s Health Initiative Steering Committee. Effects of conjugated
equine estrogen in postmenopausal women with hysterectomy: the Women’s
Health Initiative Randomized Controlled Trial. JAMA. 2004;291:1701–
36. Ahlgren M, Sorensen T, Wohlfahrt J, et al. Birth weight and risk of breast
cancer in a cohort of 106,504 women. Int J Cancer. 2003;107:997–1000.
37. Stripp C, Overvad K, Christensen J, et al. Fish intake is positively associated
with breast cancer incidence rate. J Nutr. 2003;133:3664 –3669.
38. Michels KB, Rosner BA, Chumlea WC, et al. Preschool diet and adult risk
of breast cancer. Int J Cancer. 2006;118:749 –754.
39. Monroe KR, Murphy SP, Kolonel LN, et al. Prospective study of grapefruit
intake and risk of breast cancer in postmenopausal women: the Multiethnic
Cohort Study. Br J Cancer. 2007;97:440 – 445.
40. Megdal SP, Kroenke CH, Laden F, et al. Night work and breast cancer risk:
a systemic review and meta-analysis. Eur J Cancer. 2005;41:2023–2032.
41. Schernhammer ES, Laden F, Speizer FE, et al. Rotating night shifts and risk
of breast cancer in women participating in the Nurses’ Health Study. J Natl
Cancer Inst. 2001;93:1563–1568.
42. Pukkala F, Auvinen A, Wahlberg G. Incidence of cancer among Finnish
airline cabin attendants, 1967–1992. BMJ. 1995;311:649 – 652.
43. Mawson AR. Breast cancer in female ﬂight attendants. Lancet. 1998;352:
44. Rafnsson V, Tulinius H, Jo´nasson JG, et al. Risk of breast cancer in female
ﬂight attendants: a population-based study (Iceland). Cancer Causes Con-
45. Elias SG, Peeters PH, Grobbee DE, et al. Breast cancer risk after caloric
restriction during the 1944 –1945 Dutch famine. J Natl Cancer Inst. 2004;
46. Velicer CM, Heckbert SR, Lampe JW, et al. Antibiotic use in relation to the
risk of breast cancer. JAMA. 2004;291:827– 835.
47. Kangmin Z, Hunter S, Payne-Wiks K, et al. Use of electric bedding devices
and risk of breast cancer in African-American women. Am J Epidemiol.
2003;158:798 – 806.
48. Sasco AJ, Merrill RM, Dari I, et al. A case-control study of lung cancer in
Casablanca, Morocco. Cancer Causes Control. 2002;13:609 – 616.
49. Simon R. Meta-analysis and cancer clinical trials. In: DeVita VT Jr, Hellman
S, Rosenberg SA, eds. Principles and Practice of Oncology. 3rd ed. PPO
Updates. PA: Lippincott Williams and Wilkins; 1991;5:1–10.
50. Martin B. Coincidences: remarkable or random? Skeptical Inquirer. 1998;
51. Cox DR. Another comment on the role of statistical methods. BMJ. 2001;
52. Sterne JA, Smith GD. Sifting the evidence: what’s wrong with signiﬁcance
tests? BMJ. 2001;322:226 –231.
53. Smith GD, Ebrahim S. Data dredging, bias, or confounding. BMJ. 2002;
54. Chan A, Hro´bjartsson A, Haahr MT, et al. Empirical evidence for selective
reporting of outcomes in randomized trials: comparison of protocols to
published articles. JAMA. 2004;291:2457–2465.
55. Ioannidis JP. Why most published research ﬁndings are false. PLoS Med.
56. Kraemer HC, Frank E, Kupfer DJ. Moderators of treatment outcomes:
clinical, research, and policy importance. JAMA. 2006;296:1286 –1289.
57. Boffetta P, McLaughlin JK, La Vecchia CL, et al. False-positive results in
cancer epidemiology: a plea for epistemological modesty. J Natl Cancer
Inst. 2008;100:988 –995.
58. Bernstein PL. Against the Gods: The Remarkable Story of Risk. NY: Wiley;
1996 and 1998:161.
59. ISIS-2 (Second International Study of Infarct Survival) Collaborative
Group. Aspirin’s effect on myocardial infarct mortality and astrology.
Randomized trial of intravenous streptokinase, oral aspirin, both or neither
among 17,187 cases of suspected acute myocardial infarction: ISIS-2.
Lancet. 1988;2:349 –360.
60. Feynman RP. The Meaning of It All: Thoughts of a Citizen Scientist.
Reading, MA: Helix Books/Perseus Books; 1998:71. From a series of three
lectures given in April, 1963, at the University of Washington, as part of the
John Danz Lecture Series.
61. Gambrell RD Jr, Maier RC, Sanders BJ. Decreased incidence of breast
cancer in postmenopausal estrogen-progestogen users. Obstet Gynecol.
62. Lauritzen C, Meier F. Risks of endometrial and mammary cancer morbidity
and mortality in long-term estrogen treatment. In: Herendael H, van Heren-
dael B, Riphagen FE, et al, eds. The Climacteric—An Update. Lancaster:
MTP Press; 1984:207–216.
63. Brinton LA, Hoover R, Fraumeni JF. Menopausal oestrogens and breast
cancer risk: an expanded case-control study. Br J Cancer. 1986;54:825– 832.
64. Bergkvist L, Adami HO, Persson I, et al. The risk of breast cancer after
estrogen and estrogen-progestin replacement. N Engl J Med. 1989;321:293–
65. Palmer JR, Rosenberg L, Clarke EA, et al. Breast cancer risk after estrogen
replacement therapy: results from the Toronto breast cancer study. Am J
Epidemiol. 1991;134:1386 –1395.
66. Steinberg KK, Smith SJ, Thacker SB, et al. Breast cancer risk and duration
of estrogen use: the role of study design in meta-analysis. Epidemiology.
67. Stanford JL, Weiss NS, Voight LF, et al. Combined estrogen and progestin
hormone replacement therapy in relation to risk of breast cancer in middle-
aged women. JAMA. 1995;274:137–142.
68. Wren BG. Hormonal replacement therapy and breast cancer. Eur Meno-
pause J. 1995;2:13–19.
69. Willis DB, Calle EE, Miracle-McMahill HL, et al. Estrogen replacement
therapy and risk of fatal breast cancer in a prospective cohort of postmeno-
pausal women in the United States. Cancer Causes Control. 1996;7:449 –
70. Sellers TA, Mink PJ, Ceerhan JR, et al. The role of hormone replacement
therapy in the risk for breast cancer and total mortality in women with a
family history of breast cancer. Ann Intern Med. 1997;127:973–980.
71. 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.
72. LaCroix AZ. Breast cancer and hormone replacement therapy. Lancet.
73. Lando JF, Heck KE, Brett KM. Hormone replacement therapy and breast
cancer risk in a nationally representative cohort. Am J Prev Med. 1999;17:
74. Nawaz H, Katz DL. American College of Preventive Medicine Practice
Policy Statement: perimenopausal and postmenopausal hormone replace-
ment therapy. Am J Prev Med. 1999;17:250 –254.
75. Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk
of breast cancer with a favorable histology: results of the Iowa Women’s
Health Study. JAMA. 1999;281:2091–2097.
76. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-
progestin replacement therapy and breast cancer risk. JAMA. 2000;283:485–
77. Willett WC, Colditz G, Stampfer M. Postmenopausal estrogen— opposed,
unopposed, or none of the above. JAMA. 2000;283:534 –535.
78. Ross RK, Paganini-Hill A, Wan PC, et al. Effect of hormone replacement
therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Nat
Cancer Inst. 2000;92:328 –332.
79. de Lignie`res B, de Vathaire F, Fournier S, et al. Combined hormone
replacement therapy and risk of breast cancer in a French cohort study of
3175 women. Climacteric. 2002;5:332–340.
80. Bosze P, Toth A, Torok M. Hormone replacement and the risk of breast
cancer in Turner’s Syndrome. N Engl J Med. 2006;355:2599 –2600.
81. Espie´ M, Daures J-P, Chevallier T, et al. Breast cancer incidence and
hormone replacement therapy: results from the MISSION study, prospective
phase. Gynecol Endocrinol. 2007;23:391–397.
82. Hemminki E, Kennedy DL, Baum C, et al. Prescribing of noncontraceptive
estrogens and progestins in the United States, 1974 –86. Am J Public Health.
83. Hulka BS, Chambless LE, Deubner DC, et al. Breast cancer and estrogen
replacement therapy. Am J Obstet Gynecol. 1982;143:638 – 644.
84. Bluming AZ. Hormone replacement therapy: beneﬁts and risks for the
general postmenopausal female population and for women with a history of
previously-treated breast cancer. Semin Oncol. 1993;20:662– 674.
85. Kaufman DW, Miller DR, Rosenberg L, et al. Noncontraceptive estrogen
use and the risk of breast cancer. JAMA. 1984;252:63– 67.
86. Dupont WD, Page DL, Rogers LW, et al. Inﬂuence of exogenous estrogens,
The Cancer Journal • Volume 15, Number 2, March/April 2009 HRT
© 2009 Lippincott Williams & Wilkins 101
proliferative breast disease, and other variables on breast cancer risk.
Cancer. 1989;63:948 –957.
87. 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.
88. Million Women Study Collaborators. Breast cancer and hormone-replace-
ment therapy in the Million Women Study. Lancet. 2003;362:419 – 427.
89. The Women’s Health Initiative Steering Committee. Effects of Conjugated
Equine Estrogen in Postmenopausal Women with Hysterectomy: the Wom-
en’s Health Initiative Randomized Controlled Trial. JAMA. 2004;291:1701–
90. Stefanick ML, Anderson GL, Margolis KL, et al; for the WHI Investigators.
Effects of conjugated equine estrogens on breast cancer and mammography
screening in postmenopausal women with hysterectomy. JAMA. 2006;295:
91. Takeuchi M, Saeki T, Sano M, et al; The Study Group of HRT and Breast
Cancer in Japan. Case control study of hormone replacement therapy (HRT)
and breast cancer in Japanese women. Proc ASCO 2006;24:10012.
92. Zhang SM, Manson JE, Rexrode KM, et al. Use of oral conjugated estrogen
alone and risk of breast cancer. Am J Epidemiol. 2007;165:524 –529.
93. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy
and breast cancer risk in the Women’s Health Initiative randomized trial of
estrogen plus progestin. Maturitas. 2006;55:103–115.
94. Heiss G, Wallace R, Anderson GL, et al; for the WHI Investigators. Health
risks and beneﬁts 3 years after stopping randomized treatment with estrogen
and progestin. JAMA. 2008;299:1036 –1045.
95. Eisen A, Lubinski J, Gronwald J, et al; and the Hereditary Breast Cancer
Clinical Study Group. Hormone therapy and the risk of breast cancer in
BRCA1 mutation carriers. J Natl Cancer Inst. 2008;100:1361–1367.
96. Gann PH, Morrow M. Combined hormone therapy and breast cancer: a
single-edged sword. JAMA. 2003;289:3304 –3306; quote 3304.
97. Li CI, Malone KE, Porter PL, et al. Relationship between long durations and
different regimens of hormone therapy and risk of breast cancer. JAMA.
2003;289:3254 –3263; quote 3254.
98. Anderson G. Release of the results of the Estrogen Plus Progestin Trial of
the WHI: Data and Safety Monitoring. Press Conference Remarks. WHI
Coordinating Center; July 9, 2002.
99. Hunt K, Vessey M, McPherson K, et al. Long-term surveillance of mortality
and cancer incidence in women receiving hormone replacement therapy.
Br J Obstet Gynecol. 1987;94:620 – 635.
100. Bergkvist L, Adami HO, Persson I, et al. Prognosis after breast cancer
diagnosis in women exposed to estrogens and estrogen-progestin replace-
ment therapy. Am J Epidemiol. 1989;130:221–228.
101. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of
estrogen replacement therapy. Arch Intern Med. 1991;151:75–78.
102. Strickland DM, Gambrell RD, Butzin CA, et al. The relationship between
breast cancer survival and prior postmenopausal estrogen use. Obstet Gy-
necol. 1992;80:400 – 404.
103. Bonnier P, Romain S, Giacalone PL, et al. Clinical and biologic prognostic
factors in breast cancer diagnosed during postmenopausal hormone replace-
ment therapy. Obstet Gynecol. 1995;85:11–17.
104. Harding C, Knox WF, Faragher EB, et al. Hormone replacement therapy and
tumour grade in breast cancer: prospective study in screening unit. BMJ.
105. Persson I, Yuen J, Bergkvist L, et al. Cancer incidence and mortality in
women receiving estrogen and estrogen-progestin replacement therapy—
long-term follow-up of a Swedish cohort. Int J Cancer. 1996;67:327–332.
106. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone
therapy and mortality. N Engl J Med. 1997;336:1769 –1775.
107. Schairer C, Gail M, Byrne C, et al. Estrogen replacement therapy and breast
cancer survival in a large screening study. J Natl Cancer Inst. 1999;91:264 –
108. Fowble B, Hanlon A, Greedman G, et al. Postmenopausal hormone replace-
ment therapy: effect on diagnosis and outcome in early–stage invasive breast
cancer treated with conservative surgery and radiation. J Clin Oncol.
109. Jernstrom H, Frenander J, Ferno M, et al. Hormone replacement therapy
before breast cancer diagnosis signiﬁcantly reduces the overall death rate
compared with never– use among 984 breast cancer patients. Br J Cancer.
110. Kelly PT. Assess Your True Risk of Breast Cancer. NY: Henry Holt and Co;
111. Nanda K, Bastian LA, Schulz K. Hormone replacement therapy and the risk
of death from breast cancer: a systematic review. Am J Obstet Gynecol.
112. Sacchini V, Zurrida S, Andreoni G, et al. Pathologic and biological prog-
nostic factors of breast cancers in short- and long-term hormone replacement
therapy users. Ann Surg Oncol. 2002;9:266 –271.
113. Barrett-Connor E. Postmenopausal estrogen replacement and breast cancer.
N Engl J Med. 1989;321:319 –320.
114. Harvard Medical School Health Letter. Estrogen Replacement and Breast
Cancer. Boston, MA: Harvard Medical School; 1989:14(12):1–3.
115. Bluming AZ. Breast cancer and hormone-replacement therapy. N Engl
J Med. 1995;333:1357.
116. Rebbeck TR, Levin AM, Eisen A, et al. Breast cancer risk after bilateral
prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst.
117. Rebbeck TR, Friebel T, Wagner T, et al. Effect of short-term hormone
replacement therapy on breast cancer risk reduction after bilateral prophy-
lactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE
Study Group. J Clin Oncol. 2005;23:7804 –7810.
118. Bluming AZ. HRT. The debate should continue. Geriatrics. 2004;59:30 –38.
119. Benson K, Hartz AJ. A comparison of observational studies and randomized,
controlled trials. N Engl J Med. 2000;342:1878 –1886.
120. Poynard T, Munteanu M, Ratziu V, et al. Truth survival in clinical research.
An evidence-based requiem? Ann Intern Med. 2002;136:888 – 895.
121. Liberati A, Himel HN, Chalmers TC. A quality assessment of randomized
control trials of primary treatment of breast cancer. J Clin Oncol. 1986;4:
122. Santen RJ, Pinkerton J, McCartney C, et al. Risk of breast cancer with
progestins in combination with estrogen as hormone replacement therapy.
J Clin Endocrinol Metab. 2001;86:16 –23.
123. La Vecchia C, Negri E, Bruzzi P, et al. The role of age at menarche and at
menopause on breast cancer risk: combined evidence from four case-control
studies. Ann Oncol. 1992;3:625– 629.
124. Casey PM, Cerhan JR, Pruthi S. Oral contraceptive use and risk of breast
cancer. Mayo Clin Proc. 2008;83:86 –90.
125. The Centers for Disease Control Cancer and Steroid Hormone Study.
Long-term oral contraceptive use and the risk for breast cancer. JAMA.
126. Vessey M, Baron J, Doll R, et al. Oral contraceptives and breast cancer: ﬁnal
report of an epidemiological study. Br J Cancer. 1983;7:455– 462.
127. The Cancer and Steroid Hormone Study of the Centers for Disease Control
and the National Institutes of Child Health and Human Development.
Oral-contraceptive use and the risk of breast cancer. N Engl J Med.
128. Murray PP, Staedel BV, Schlessesman JJ. Oral contraceptive use in women
with a family history of breast cancer. Obstet Gynecol. 1989;73:977–983.
129. Vessey MP, McPherson K, Villard-Mackintosh L, et al. Oral contraceptives
and breast cancer: latest ﬁndings in a large cohort study. Br J Cancer.
130. Stanford JL, Brinton LA, Hoover RN. Oral contraceptives and breast cancer:
results from an expanded case control study. Br J Cancer. 1989;60:375–381.
131. Romieu I, Willett WC, Colditz GA, et al. Prospective study of oral contra-
ceptive use and risk of breast cancer in women. J Natl Cancer Inst.
132. Romieu I, Berlin JA, Colditz G. Oral contraceptives and breast cancer:
review and meta-analysis. Cancer. 1990;66:2253–2263.
133. White E, Malone KE, Weiss NS, et al. Breast cancer among young U.S.
women in relation to oral contraceptive use. J Natl Cancer Inst. 1994;86:
134. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and
the risk of breast cancer. N Engl J Med. 2002;346:2025–2032.
135. Davidson NE, Helzlsouer KJ. Good news about oral contraceptives. N Engl
J Med. 2002;346:2078 –2079.
136. Claus EB, Stowe M, Carter D. Oral contraceptives and the risk of ductal
breast carcinoma in situ. Breast Cancer Res Treat. 2003;81:129 –136.
137. Silvera SA, Miller AB, Rohan TE. Oral contraceptive use and risk of breast
cancer among women with a family history of breast cancer: a prospective
cohort study. Cancer Causes Control. 2005;16:1059 –1063.
138. Gill JK, Press MF, Patel AV, et al. Oral contraceptive use and risk of breast
carcinoma in situ (United States). Cancer Causes Control. 2006;17:1155–
139. Hannaford PC, Selvaraj S, Elliott AM, et al. Cancer risk among users of oral
contraceptives: cohort data from the Royal College of General Practitioner’s
oral contraception study. BMJ. 2007;335:651.
140. Figueiredo JC, Bernstein L, Capanu M, et al. Oral contraceptives, postmeno-
pausal hormones, and risk of asynchronous bilateral breast cancer: the
WECARE Study Group. J Clin Oncol. 2008;26:1411–1418.
141. Wingo PA, Austin H, Marchbanks PA, et al. Oral contraceptives and the risk
of death from breast cancer. Obstet Gynecol. 2007;110:793– 800.
142. Henderson IC. Risk factors for breast cancer development. Cancer. 1993;
143. Madigan M, Ziegler R, Benichou C, et al. Proportion of breast cancer cases
in the United States explained by well-established risk factors. J Natl Cancer
144. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2008. CA Cancer J Clin.
Bluming and Tavris The Cancer Journal • Volume 15, Number 2, March/April 2009
© 2009 Lippincott Williams & Wilkins102
145. Workshop report from the Division of Cancer Etiology, National Cancer
Institute, NIH. Current perspectives and future trends in hormonal carcino-
genesis. Cancer Res. 1991;51:3626 –3629.
146. Thomas DB. Do hormones cause breast cancer? Cancer. 1984;53:595– 604.
147. Clarke RB, Howell A, Potten CS, et al. Dissociation between steroid
receptor expression and cell proliferation in the human breast. Cancer Res.
148. Sleeman KE, Kendrick H, Robertson D, et al. Dissociation of estrogen
receptor expression and in vivo stem cell activity in the mammary gland.
The Breakthrough Cancer Research Centre, Institute of Cancer Research,
London. J Cell Biol. 2007;176:19 –26.
149. Lewis JS, Jordan VC. Selective estrogen receptor modulators (SERMs):
mechanisms of anticarcinogenesis and drug resistance. Mutat Res. 2005;
150. Ravdin PM, Fritz NF, Tormey DC, et al. Endocrine status of premenopausal
node-positive breast cancer patients following adjuvant chemotherapy and
long-term tamoxifen. Cancer Res. 1988;48:1026 –1029.
151. Cobleigh M. Hormone replacement therapy in breast cancer survivors. In:
Harris JR, Lippman ME, Morrow M, et al, eds. Diseases of the Breast. 2nd
ed. Philadelphia: Lippincott Williams and Wilkins; 1997:1–10.
152. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial
evaluating tamoxifen in the treatment of patients with node-negative breast
cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989;
320:479 – 484.
153. The Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early
breast cancer: an overview of the randomized trials. Lancet. 1998;351:1451–
154. Gee JM, Robertson JF, Gutteridge E, et al. Epidermal growth factor
receptor/HER2/insulin-like growth factor receptor signalling and oestrogen
receptor activity in clinical breast cancer. Endocr Relat Cancer. 2005;
12(suppl 1):S99 –S111.
155. Lam HY. Tamoxifen is a calmodulin antagonist in the activation of cAMP
phosphodiesterase. Biochem Biophys Res Commun. 1984;118:27–32.
156. Mandeville R, Ghali SS, Chausseau JP. In vitro stimulation of human NK
activity by an estrogen antagonist (tamoxifen). Eur J Cancer Clin Oncol.
157. O’Brian CA, Liskamp RM, Solomon DH, et al. Inhibition of protein kinase
C by tamoxifen. Cancer Res. 1985;45:2462–2465.
158. Borley AC, Hiscox S, Gee J, et al. Anti-oestrogens but not oestrogen
deprivation promote cellular invasion in intercellular adhesion-deﬁcient
breast cancer cells. Breast Cancer Res. 2008;10:R103.
159. Vignon F, Bouton MM, Rochefort H. Antiestrogens inhibit the mitogenic
effect of growth factors on breast cancer cells in the total absence of
estrogens. Biochem Biophys Res Commun. 1987;146:1502–1508.
160. Howell A, Dodwell DJ, Anderson H, et al. Response after withdrawal of
tamoxifen and progestogens in advanced breast cancer. Ann Oncol. 1992;3:
161. Yao K, Lee ES, Bentrem DJ, et al. Antitumor action of physiologic estradiol
on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer
Res. 2000;6:2028 –2036.
162. Liu H, Lee ES, Gajdos C, et al. Apoptotic action of 17 b-estradiol in
raloxifene-resistant MCF-7 cells in vitro and in vivo. J Natl Cancer Inst.
163. Lewis JS, Meeke K, Osipo C, et al. Intrinsic mechanism of estradiol-induced
apoptosis in breast cancer cells resistant to estrogen deprivation. J Natl
Cancer Inst. 2005;97:1746 –1759.
164. Jordan VC. The 38th David A. Karnovsky lecture: the paradoxical actions of
estrogen in breast cancer—survival or death? J Clin Oncol. 2008;26:1–10.
165. Scandlyn MJ, Stuart EC, Somers-Edgar TJ, et al. A new role for tamoxifen
in oestrogen receptor-negative breast cancer when it is combined with
epigallocatechin gallate. Br J Cancer. 2008;99:1056 –1063.
166. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med.
167. Jordan VC, Gapstur S, Morrow M. Selective estrogen receptor modulation
and reduction in risk of breast cancer, osteoporosis, and coronary heart
disease. J Natl Cancer Inst. 2001;93:1449 –1457.
168. Barrett-Connor E, Bush TL. Estrogen replacement and coronary heart
disease. Cardiovasc Clin. 1989;19:159 –172.
169. Goldman L, Tosteson AN. Uncertainty about postmenopausal estrogen.
Time for action, not debate. N Engl J Med. 1991;325:800 – 802.
170. Grodstein F, Manson JE, Colditz GA, et al. A prospective observational
study of postmenopausal hormone therapy and primary prevention of car-
diovascular disease. Ann Intern Med. 2000;133:933–941.
171. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus
progestin for secondary prevention of coronary heart disease in postmeno-
pausal women. Heart and Estrogen/progestin Replacement Study (HERS)
Research Group. JAMA. 1998;280:605– 613.
172. Shapiro S. Risk of estrogen plus progestin therapy: a sensitivity analysis of
the ﬁndings in the Women’s Health Initiative randomized controlled trial.
173. Rossouw JE, Prentice RI, Manson JE, et al. Postmenopausal hormone
therapy and risk of cardiovascular disease by age and years since meno-
pause. JAMA. 2007;297:1465–1477.
174. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart
disease: the role of time since menopause and age at hormone initiation.
J Womens Health. 2006;15:35– 44.
175. Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis,
and vascular function. Cardiovasc Res. 2002;53:605– 619.
176. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen
replacement on the progression of coronary artery atherosclerosis. N Engl
J Med. 2000;343:522–529.
177. Hodis HJ, Mack WJ, Lobo RA, et al. Estrogen in the prevention of
atherosclerosis. Ann Intern Med. 2001;135:939 –953.
178. Bhavnani BR, Strickler RC. Menopausal hormone therapy. J Obstet Gynae-
col Can. 2005;27:137–162.
179. Mastorakos G, Sakkas EG, Xydakis AM, et al. Pitfalls of the WHI’s
women’s health initiative. Ann NY Acad Sci. 2006;1092:331–340.
180. Foy MR, Henderson VW, Berger TW, et al. Estrogen and neural plasticity.
Curr Dir Psychol Sci. 2000;9:148 –152.
181. Alkayed NJ, Murphy SJ, Traystman RJ, et al. Neuroprotective effects of
female gonads steroids in reproductively senescent female rats. Stroke.
182. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of
Alzheimer disease. Arch Intern Med. 1996;156:2213–2217.
183. Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause
on risk and age at onset of Alzheimer’s disease. Lancet. 1996;348:429 – 432.
184. Simpkins JW, Green PS, Gridley KE, et al. Role of estrogen replacement
therapy in memory enhancement and the prevention of neuronal loss
associated with Alzheimer’s disease. Am J Med. 1997;103:19s–25s.
185. Rice MM, Graves AB, McCurry SM, et al. Estrogen replacement therapy
and cognitive function in postmenopausal women without dementia. Am J
186. Birge SJ. The role of ovarian hormones in cognition and dementia. Neurol-
ogy. 1997;48(suppl 7):81.
187. Sherwin BB. Estrogen and cognitive functioning in women. Proc Soc Exp
Biol Med. 1998;217:17–21.
188. Shaywitz SE, Shaywitz BA, Pugh KR, et al. Effect of estrogen on brain
activation patterns in postmenopausal women during working memory
tasks. JAMA. 1999;281:1197–1202.
189. Yang SH, Shi J, Day AL, et al. Estradiol exerts neuroprotective effects when
administered after ischemic insult. Stroke. 2000;31:745–750.
190. Yaffe K, Lui LY, Grady D, et al. Cognitive decline in women in relation to
non-protein-bound oestradiol concentrations. Lancet. 2000;356:708 –712.
191. Mayeux R. Can estrogen or selective estrogen-receptor modulators preserve
cognitive function in elderly women? N Engl J Med. 2001;344:1242–1244.
192. Shepherd JE. Effects of estrogen on cognition, mood, and degenerative brain
diseases. J Am Pharm Assoc. 2001;41:221–228.
193. LeBlanc ES, Janowsky J, Chan BK, et al. Hormone replacement therapy and
cognition: systematic review and meta-analysis. JAMA. 2001;285:1489 –
194. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy
and incidence of Alzheimer disease in older women: the Cache County
Study. JAMA. 2002;288:2123–2129.
195. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer
disease: a critical time. JAMA. 2002;288:2170 –2172.
196. Nilsen J, Brinton RD. Mechanism of estrogen-mediated neuroprotection:
regulation of mitochondrial calcium and Bcl-2 expression. Proc Natl Acad
197. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the
incidence of dementia and mild cognitive impairment in postmenopausal
women. The Women’s Health Initiative memory study: a randomized
controlled trial. JAMA. 2003;289:2651–2662.
198. Shumaker SA, Legault C, Kuller L, et al. Conjugated estrogens and inci-
dence of probable dementia and mild cognitive impairment in postmeno-
pausal women. JAMA. 2004;291:2947–2958.
199. Hays J, Ockene JK, Brunner RL, et al; for the Women’s Health Initiative
Investigators. Effects of estrogen plus progestin on health-related quality of
life. N Engl J Med. 2003;348:1839 –1854.
200. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer
incidence in 2003 in the United States. N Engl J Med. 2007;356:1670 –1674.
201. Stewart SL, Sabatino SA, Foster SL, et al. Decline in breast cancer
incidence-United States, 1999 –2003. MMWR Weekly. 2007;56:549–553.
202. MacMahon B, Cole P. Is the incidence of breast cancer declining? Epide-
miology. 2008;19:268 –269.
203. Gershon-Cohen J, Merger SM, Klickstein HS. Roentgenography of breast
cancer moderating concept of “biologic predeterminism.” Cancer. 1963;16:
204. Speer JF, Petrosky VE, Retsky MW, et al. A stochastic numerical model of
breast cancer growth that simulates clinical data. Cancer Res. 1984;44:124 –
The Cancer Journal • Volume 15, Number 2, March/April 2009 HRT
© 2009 Lippincott Williams & Wilkins 103
205. von Fournier D, Hoefken W, Jundermann H, et al. Growth rate of primary
mammary carcinoma and its metastases. In: Zander J, Baltzer J, eds. Early
Breast Cancer. Berlin, Heidelberg: Springer Verlag; 1985:73– 86.
206. Heiss G, Wallace R, Anderson GL, et al; for the WHI Investigators. Health
risks and beneﬁts 3 years after stopping randomized treatment with estrogen
and progestin. JAMA. 2008;299:1036 –1045.
207. Col NF, Eckman MH, Karas RH, et al. Patient-speciﬁc decisions about
hormone replacement therapy in postmenopausal women. JAMA. 1997;277:
208. Grodstein F, Martinez E, Platz EA, et al. Postmenopausal hormone use and
risk for colorectal cancer and adenoma. Ann Intern Med. 1998;128:705–712.
209. Paganini-Hill A. Estrogen replacement therapy and colorectal cancer risk in
elderly women. Dis Colon Rectum. 1999;42:1300 –1305.
210. Hammond AL. Editorial introduction. Science 80. July/August 1980.
Bluming and Tavris The Cancer Journal • Volume 15, Number 2, March/April 2009
© 2009 Lippincott Williams & Wilkins104