Here's an excerpt from a much longer article published in The Cancer Journal:
. . . But what about drugs like tamoxifen, an “estrogen antagonist,” (ME: estrogen receptor blocker) which are given to breast-cancer patients to reduce the chance of recurrence? One of the arguments that estrogen causes or promotes 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.149
However, several lines of research dispute this belief. For one thing, when tamoxifen is given to premenopausal women, their natural estrogen levels increase up to 5-fold.150 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 postmenopausal women.151–153
Second, approximately 40% of ER positive patients fail to respond to
tamoxifen.154
Third, laboratory studies have shown that tamoxifen inhibits the
stimulatory effects of growth factors involved in breast cancer155–158
even in the absence of estrogen.159 In addition, after treatment with
tamoxifen, some breast cancer cells actually acquire the ability to
proliferate160—and low doses of estrogen have been shown capable
of killing them.161–164
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.165
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 unknown,
166,167 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.
__________________________________________________________
I know this may sound like gobbledygook if you haven't been immersed in HRT/breast cancer research stuff like I have been, but it DOES help to explain why the conventional idea that estrogen is "evil" (and must be blocked if you have breast cancer) is way too simplistic. And that simplistic viewpoint has caused HUGE amounts of suffering for thousands upon thousands of women whose quality of life, when deprived of the estrogen that they so desperately need, plummets (sometimes taking them straight down into the depths of hell itself).
Full article:
REVIEW ARTICLE
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 increased 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)a 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.1 This increased risk is
eliminated when progestin is added.2b Estrogen replacement therapy (ERT) alone is thus generally given only to women who have had hysterectomies.
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.3–9 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.10–18 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%.19–24 Given that alternative medications—bisphosphonates such as Fosomax, 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 Laboratories aggressively began marketing their estrogen preparation, Premarin, 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.25 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.26
The 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 medicine’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%.27
DATA DREDGING, RISK REPORTING, AND OTHER PROBLEMS IN RESEARCH
Should women who have menopausal symptoms deny themselves
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 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
definitive answer.28 Yet the news-hungry media crave “breakthroughs” 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 research 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 example, 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 statistical convention but which, in practical terms, means little or nothing because of the low absolute numbers.29
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.30 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.31–33 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 with HRT25,34 and ERT35 but also with birth weight,36 fish intake,37 eating 1 additional serving of French fries per week during preschool years,38 eating grapefruit,39 working on a night shift,40,41 working as an airline flight attendant in 2 different airlines,42–44 suffering from severe caloric restriction during the 1944–1945 Dutch famine,45 taking antibiotics,46 and the use of electric blankets by African-American women.47 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.48 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 substratification, commonly known as “data mining” or “data dredging.” 49–56 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.
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.”57
In Against the Gods: The Remarkable Story of Risk, the economist Peter Bernstein put it this way: “If you torture the data long enough, the numbers will prove anything you want.”58
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.”59
Richard Feynman,60 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 obviously.”
The relationship between cigarette smoking and lung cancer
is an example of the truth becoming clearer with repeated observations: 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.29,48 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.61–81 Table 2 reviews the highlights of research from the first manufacture of estrogen tablets (Premarin) in 1942 tothe 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 the Women’s Health
Initiative of the risk and benefits of combined estrogen and progestin 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.25 (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 nominal statistical significance.” “Almost” means it did not reach statistical 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 Morrow96 wrote: “A
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.
Garnet Anderson98, coprincipal 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. In addition, 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.70,99–112
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.34
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 “significant” relative risk had completely vanished.93 This news did not make headlines.
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.64 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, Sweden, 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 significant
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,113 in an editorial accompanying 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 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.”114 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 rosacea46 (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 time45; 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.47
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.76
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, unreplicated 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.87 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 developing breast cancer falls by half. But the surgery induces menopause, and some patients subsequently take HRT to alleviate menopausal 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
menopause.95
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 symptoms, right? Yet, according to another large-scale study and its own follow-up, administering estrogen to women with BRCA1 mutations, following removal of the women’s ovaries, did not nullify the benefits of the surgery. Their risk of breast cancer remained just as low.116,117
Moreover, the majority of observational studies have found
no increased risk of breast cancer associated with HRT,84,118 including studies in which HRT was given to women with a family history of breast cancer.70,86 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 outcomes.119 Another review found that the persistent validity of conclusions 20 years after initial publication was 87% among nonrandomized (observational) trials and 85% among randomized clinical trials.120
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.121 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%.122 (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 cancer. 101,106 How can the very hormones that allegedly increase the risk of breast cancer also be responsible for a better survival rate from that cancer?
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.115
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 combined HRT was associated with a statistically nonsignificant 26% increase in breastcancer risk.”97 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.)
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.123 These observations suggested, reasonably, 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:
- Birth 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,124 most published studies find that oral contraceptives do not increase the risk.125–141
- Women 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 breast-cancer risk.90
- The 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.142–144
- According to the National Cancer Institute’s Division of CancerEtiology, estrogens are not direct carcinogens for mammary cells.145 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 proliferating cell will be exposed to a mutagen and become malignant. 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 prolonged 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.146
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 dangerous 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.147,148
But what about drugs like tamoxifen, an “estrogen antagonist,”
which are given to breast-cancer patients to reduce the chance
of recurrence? One of the arguments that estrogen causes or promotes 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.149 However, several lines of research dispute this belief. For one thing, when tamoxifen is given to premenopausal women, their natural estrogen levels increase up to 5-fold.150 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 postmenopausal women.151–153
Second, approximately 40% of ER positive patients fail to respond to tamoxifen.154
Third, laboratory studies have shown that tamoxifen inhibits the stimulatory effects of growth factors involved in breast cancer155–158 even in the absence of estrogen.159 In addition, after treatment with tamoxifen, some breast cancer cells actually acquire the ability to proliferate160—and low doses of estrogen have been shown capable of killing them.161–164
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.165 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 unknown, 166,167 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 AND STROKE
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.144 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.168 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 therapy. 169 In 2000, the Nurses’ Health Study reported that HRT reduced the development of primary cardiovascular disease by nearly 40%,170 a condition responsible for more than 300,000 deaths among US women per year.144
Subsequently, a large randomized study, the Heart and Estrogen/
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.171 In
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 infarction
requiring hospitalization or silent myocardial infarction), death
because of heart disease, angina, or indications for revascularization
surgery.25 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.172g In 2007, the WHI investigators
g 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.
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.173 In another confluence of a
randomized trial and an observational study, the Nurses’ Health
Study reached the same conclusions.174
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.175 The Estrogen Prevention of Atherosclerosis
Trial and Estrogen Replacement and Atherosclerosis studies
are consistent with the animal data.176,177 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. However,
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.25 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 because,
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.178 Yet women with these wellestablished
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 primary-
prevention study; these assertions are difficult to reconcile
with the actual medical histories of so many of the women.
Our conclusions are:
Y HRT 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.
Y HRT probably has no protective effect on women who begin
the use of HRT later, in their mid-60s.
Y HRT is potentially risky for women who begin taking it in their
60s, at least for the first year, especially if they have preexisting
artery disease.
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-grabbing,
fear-inducing story from the WHI. In 2004, the WHI announced
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.89 However, the WHI investigators had an
extremely broad definition of “stroke”—including transient, “subtle
neurologic deficits” that resolved in a day or two. Some epidemiologists
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 hormones,
had become hyperalert to any symptoms. Indeed, when these
critics reanalyzed the findings, controlling for detection bias, the
increased risk of stroke vanished.179
COGNITIVE FUNCTIONING AND ALZHEIMER’S DISEASE
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.180–196
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 conclusion
that the risks of HRT outweighed any possible benefits.197 The
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
impairment.89 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.198 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 investigators
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 menopausal
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.199 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
symptoms!
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 impairment,
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
WHI publication.200 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
findings.201,202 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.203–205 It
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.200
SUMMARY
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 blankets,
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 associations
were statistically significant.206 Other investigators, though,
feel just as strongly that the potential health benefits of postmenopausal
estrogen replacement, as measured by decreased morbidity
and increased life expectancy—by nearly 4 years, in 1 assessment—
far exceed the risks.207 Even the WHI confirmed previously published
reports of decreased risks of osteoporotic fractures and colon
cancer for women on HRT.208,209
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 menopause
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
L. Hammond,210 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 important
to read the fine print. Sometimes there is even good news there.
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.1
Mid 1980s: The addition of progestin to estrogen negates the increased risk of uterine cancer associated with estrogen alone.2 By 1986, over 20 million
prescriptions for non-contraceptive hormones are dispensed.82
1982: A study finds that estrogen is not associated with an increased risk of breast cancer.83
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.84
1984: A study reports that estrogen does not increase the risk of breast cancer, even when taken for many years.85
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.64
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
conditions.86
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.26
1995: A study reports no increased risk of breast cancer in postmenopausal women on HRT, even after more than 15 yr of use.67
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.87
1996: A study reports that ever-use of estrogen replacement therapy is associated with a slightly decreased risk of fatal breast cancer.69
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.70
2000: A study reports a 40% increased risk of breast cancer associated with HRT.76 However, this risk is limited to women weighing no more than 90
pounds.
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.78
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.25
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.37
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.88
2004: The WHI reports no increased risk of breast cancer associated with the use of estrogen alone.89
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.90
2006: A study of 9000 Japanese women finds that HRT users are less likely to develop breast cancer than never-users.91
2006: A study reports no increase in breast cancer incidence among women who have been taking estrogen, even after 8 or more years.92
2006: The WHI now reports no increased risk of breast cancer even among women randomized to take combined estrogen and progestin.93
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.94
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.95
ACKNOWLEDGMENTS
This article was written at the suggestion of the American
Council of Science and Health, whose panel of reviewers provided
many helpful suggestions
REFERENCES
1. Weiss NS. Editorial: risks and benefits of estrogen use. N Engl J Med.
1975;293:1200 –1202.
2. Gambrell RD Jr. Use of progestogen therapy. Am J Obstet Gynecol.
1987;156:1304 –1313.
3. Cauley JA, Cummings SR, Black DM, et al. Prevalence and determinants of
estrogen replacement therapy in elderly women. Am J Obstet Gynecol.
1990;163:1438 –1444.
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 therapy:
estimates from a nationally representative cohort study. Am J Epidemiol.
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.
1999;130:545–553.
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.
1999;6:307–311.
8. Ettinger B, Pressman A. Continuation of postmenopausal hormone replacement
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: determinants
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.
2002;100:1209 –1218.
13. MacLennan A, Lester A, Moore V. Oral Oestrogen Replacement Therapy
Versus Placebo for Hot Flushes. Cochrane Review on CD-ROM. 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 symptoms.
Ann Intern Med. 2005;142:1003–1013.
15. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms
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.
2006;12:115–125.
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.
1980;303:1195–1198.
20. Consensus Development Conference: Prophylaxis and treatment of osteoporosis.
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;
317:1169 –1174.
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–
1037.
23. Belchetz PE. Hormonal treatment of postmenopausal women. N Engl J Med.
1994;330:1062–1071.
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:
321–333.
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:
47–53.
Bluming and Tavris The Cancer Journal • Volume 15, Number 2, March/April 2009
100 © 2009 Lippincott Williams & Wilkins
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;
8:53–96.
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 Randomized
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–
1712.
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:
626.
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 Control.
2001;12:95–101.
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;
96:539 –546.
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;
22:23–28.
51. Cox DR. Another comment on the role of statistical methods. BMJ. 2001;
322:231.
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;
325:1437–1438.
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.
2005;2:e124.
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.
1983;62:435– 438.
62. Lauritzen C, Meier F. Risks of endometrial and mammary cancer morbidity
and mortality in long-term estrogen treatment. In: Herendael H, van Herendael
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–
297.
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.
1994;5:415– 421.
67. Stanford JL, Weiss NS, Voight LF, et al. Combined estrogen and progestin
hormone replacement therapy in relation to risk of breast cancer in middleaged
women. JAMA. 1995;274:137–142.
68. Wren BG. Hormonal replacement therapy and breast cancer. Eur Menopause
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 postmenopausal
women in the United States. Cancer Causes Control. 1996;7:449–
457.
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.
1997;350:1042–1043.
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:
176–180.
74. Nawaz H, Katz DL. American College of Preventive Medicine Practice
Policy Statement: perimenopausal and postmenopausal hormone replacement
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 estrogenprogestin
replacement therapy and breast cancer risk. JAMA. 2000;283:485–
491.
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.
1988;78:1479 –1481.
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-replacement
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 Women’s
Health Initiative Randomized Controlled Trial. JAMA. 2004;291:1701–
1712.
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:
1647–1657.
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 replacement
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 Gynecol.
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 replacement
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.
1996;312:1646 –1647.
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–
270.
108. Fowble B, Hanlon A, Greedman G, et al. Postmenopausal hormone replacement
therapy: effect on diagnosis and outcome in early–stage invasive breast
cancer treated with conservative surgery and radiation. J Clin Oncol.
1999;17:1680 –1688.
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.
1999;80:1453–1458.
110. Kelly PT. Assess Your True Risk of Breast Cancer. NY: Henry Holt and Co;
2000.
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.
2002;186:325–324.
112. Sacchini V, Zurrida S, Andreoni G, et al. Pathologic and biological prognostic
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.
1999;91:1475–1479.
117. Rebbeck TR, Friebel T, Wagner T, et al. Effect of short-term hormone
replacement therapy on breast cancer risk reduction after bilateral prophylactic
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:
942–951.
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.
1983;249:1591–1595.
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.
1986;315:405– 411.
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.
1989;59:613– 617.
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 contraceptive
use and risk of breast cancer in women. J Natl Cancer Inst.
1989;81:1313–1321.
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:
505–514.
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–
1162.
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, postmenopausal
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;
71:2127–2140.
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
Inst. 1995;87:1681–1685.
144. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2008. CA Cancer J Clin.
2008;58:71–96.
Bluming and Tavris The Cancer Journal • Volume 15, Number 2, March/April 2009
102 © 2009 Lippincott Williams & Wilkins
145. Workshop report from the Division of Cancer Etiology, National Cancer
Institute, NIH. Current perspectives and future trends in hormonal carcinogenesis.
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.
1997;57:4987– 4991.
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;
591:247–263.
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–
1467.
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.
1984;20:983–985.
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:
611–617.
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.
2003;95:1586 –1597.
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.
1998;339:1609 –1618.
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 cardiovascular
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 postmenopausal
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.
Climacteric. 2003;6:302–310.
173. Rossouw JE, Prentice RI, Manson JE, et al. Postmenopausal hormone
therapy and risk of cardiovascular disease by age and years since menopause.
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 Gynaecol
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.
2000;31:161–168.
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
Med. 1997;103:26s–35s.
186. Birge SJ. The role of ovarian hormones in cognition and dementia. Neurology.
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–
1499.
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
Sci. 2003;100:2842–2847.
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 incidence
of probable dementia and mild cognitive impairment in postmenopausal
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? Epidemiology.
2008;19:268 –269.
203. Gershon-Cohen J, Merger SM, Klickstein HS. Roentgenography of breast
cancer moderating concept of “biologic predeterminism.” Cancer. 1963;16:
961–964.
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–
130.
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:
1140–1147.
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 104 © 2009 Lippincott Williams & Wilkins
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 protected].
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 psychology
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
ISSN: 1528-9117/09/1502-0093
a 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 “replacement”
implies recommendation of this treatment. Our own preference would be
to replace HRT with “menopausal hormone therapy.”
b Progestin is the generic term for molecules that bind to and activate progesterone
receptors; it includes progesterone and synthetic derivatives such as medroxyprogesterone
acetate.
The Cancer Journal • Volume 15, Number 2, March/April 2009 93
Loved your post Jane. It is a difficult subject to get people to take interest in as it is complex and not "byte-sized" enough to generate the media attention it deserves. I so admire those who chose NOT to allow their Dr. "God-status", and wade courageously into the rivers of bullshit in search of the truth. I remember something Scott said to me several years before he passed away,"They will never find a cure for Aids". When I asked him why he believed this was the case he replied,"There's no money in it".
Posted by: Jay | Wednesday, December 29, 2010 at 08:24 AM
Yes, it is a great article about "The Hormone Hoax" that has been perpetrated on us.
The number of women suffering won't be measured until this information is exposed.
We need the info to go viral.
Posted by: Lynne | Wednesday, December 29, 2010 at 07:37 AM
Thanks for posting this, Jane. I reposted it on my Facebook page in hopes that even one person will read it. I have tried to explain this before only to get looks like I am crazy or something. Maybe if it is coming from an official medical source, it will be taken more seriously?! We can only hope....
Posted by: Jill | Tuesday, December 28, 2010 at 03:00 PM