Download Cancer Risk and the HRT Decision: Bringing It

Cancer Risk and the HRT Decision: Bringing It Down to Basics
F. J. Montz, MD, K.M.
Professor and Director
The Kelly Gynecologic Oncology Service
Departments of Gynecology and Obstetrics, and Oncology
The Johns Hopkins Hospital and Medical Institutions
Baltimore, Maryland
To take HRT or not to take HRT—that, it seems, is the endlessly repeated question.
Do the benefits really outweigh the risks, or is the opposite true? For millions of periand postmenopausal women and their clinicians, this is far more than a theoretical
question; it is a potentially life-altering one, and one that is steeped in controversy.
To fully appreciate the potential impact of any decision that a woman and her
healthcare provider may make regarding HRT, it is essential to understand the
magnitude of this relatively new issue. At the beginning of the 20th century, the
average life expectancy of an American woman was only 40 years. It is now
approaching nine decades. This exponential increase in the length of life leads to the
following realities: the average American woman will spend one third of her life in a
state of relative hypoestrogenism; 60 million American women either will be
menopausal or will enter menopause in the next few years; and living American
women can anticipate a combined total of 1.8 billion years of menopause.
Hypoestrogenism leads to both "life-threatening" and "lifestyle-threatening"
processes—and hot flashes, once the sine qua non of menopause, are turning out to
be the least of the problems. Increased risk of cardiovascular disease, osteoporosis,
Alzheimer's disease, anxiety, depression, emotional changes, fatigue, poor memory
and concentration, sleep disorders, cutaneous changes, urinary incontinence and
pelvic floor prolapse, and dyspareunia are just some of the hypoestrogenic sequelae
with which postmenopausal women potentially must deal.
Every decision made by thinking humans includes an assessment of risk as balanced
against benefit. In most situations, this risk-benefit assessment is performed
subliminally. By contrast, the risk-benefit assessment that precedes the decision to
take HRT is a more cognitive and, one would hope, a more rational one. A growing
body of data supports the beneficial effects of HRT in preventing or controlling the
life-threatening and lifestyle-threatening processes just noted. Yet a large proportion
of women who could be helped by such therapy refuse to even start HRT.
Furthermore, among those who do start HRT, it has been estimated that 20% will stop
taking it within 9 months, 10% will take it only intermittently, and as many as 30% will
never even have their prescriptions filled.1
If the benefits of HRT are so substantial, why don't more women take it?
Unquestionably, a significant cause of noncompliance is the related side effects, with
withdrawal bleeding being the most unappealing for the majority of women.2 Another
common, if not the most common, reason cited by women declining hormone
replacement is the fear of developing an HRT-related malignancy.1 Is this fear
founded on reliable data, or does it border on paranoia? And is the risk of
HRT-related cancer a real one, or has it been overblown? The answer is that in most
settings, and when taken appropriately, HRT has a protective effect at best, and a
neutral effect at worst, against four forms of cancer: endometrial, breast, ovarian, and
colon.
Endometrial cancer
The association between endometrial cancer and estrogen replacement is by now
unequivocal: If estrogen replacement is administered to a woman who has a uterus
with absent or insufficient concomitant progesterone therapy, her relative risk (RR) of
developing endometrial cancer is increased as much as 12 to 18 fold.3 However, and
most importantly, addition of an adequate dosage of progestins throughout the cycle
reduces the relative risk to below that of women who take no hormone replacement at
all.3 Secondary to the salutary effects of HRT, women who develop endometrial
cancer while receiving HRT have a longer life expectancy than do women who neither
develop endometrial cancer nor take HRT.
Breast cancer
The 1-in-8-lifetime breast cancer risk figure has been well publicized4; most women
can recite it readily. What women tend to be less aware of is that it is heart disease,
not breast cancer, that kills the greatest number of American women each year. More
American women die of heart disease than of any other cause, including breast
cancer.5 Thus, while breast cancer tends to be what women fear most, the fact is that
they have far more to fear from heart disease.
This fact notwithstanding, fear of breast cancer continues to prevent a substantial
number of women from taking HRT. Is the fear founded in fact? As matters currently
stand, the vast majority of large, well-designed studies evaluating HRT and the risk of
breast cancer have failed to identify an increase in RR in the average-risk population.6
However, it must be acknowledged that there are some data to suggest that selected
subgroups of women who take HRT (those who take relatively high doses of estrogen
for long time periods, those with a history of prior proliferative, nonmalignant breast
disease, thin women receiving certain progestins, and those with family histories of
breast cancer) are at a statistically significant increased risk of developing breast
cancer.7,8 Interestingly, however, those patients who develop breast cancer while
receiving HRT have been repeatedly demonstrated to have higher rates of
disease-free survival than similar patients who develop breast cancer while not taking
HRT. This difference persists when controlled for stage of disease, and may be
secondary to a higher percentage of less aggressive breast cancer subtypes being
diagnosed in women taking HRT.9
This issue is not without controversy, but we can be certain of a few things. First,
hormone replacement has been used for more than five decades in the United States,
and more than 1,500 peer-reviewed journal articles have examined the association
between HRT and breast cancer development. The mere fact that this enormous body
of literature has not produced a clear answer is reassuring in and of itself: if the
association between HRT and breast cancer was strong and real, we should have
more than enough objective data to substantiate it, just as we do for the association
between endometrial cancer and unopposed estrogen administration. Secondly, from
a public health perspective, it is clear that more women-years are saved as a result of
the beneficial effects of HRT than are lost from the negative effects of a potential
increase in RR of developing breast cancer.10
Ovarian cancer
There have been no randomized clinical trials examining the potential association
between HRT and ovarian cancer, and there is a paucity of reliable historical data.
However, most of the existing research suggests no increase in risk. A rare exception
is a recent meta-analysis that showed an overall RR of 1.15 in ever-users of HRT.11
It is not theoretically implausible that HRT might stimulate the ovarian epithelium and
thereby increase a woman's risk of developing ovarian cancer. At the same time,
however, one must ask whether this increase in risk is clinically significant. It is true
that survival rates are not high for this form of cancer. On the other hand, relative to the
risk of developing cardiovascular disease in women, the risk of developing ovarian
cancer is very low—just 1.5% in the course of a lifetime.12 Thus, for ovarian cancer, as
in the case of breast cancer, the proven overall benefits of HRT outweigh the potential
risks, when the aggregate of clinical data is measured objectively.
Colon cancer
The data regarding HRT and colon cancer are relatively conclusive: The risk of this
form of cancer is reduced by 50% in recent HRT users. Moreover, the longer the
duration of use, the greater the protection; even a remote history of HRT use (up to 10
years before) can impart a protective effect.13,14 In answer to the question we
considered for ovarian cancer—Is this decrease in risk clinically significant?—one
would have to conclude that it is, since women in the United States are almost three to
four times more likely to develop colon cancer than they are ovarian cancer.12
Conclusion
For the majority of American women, the cancer-phobic concerns that lead to
avoidance of postmenopausal HRT are neither rational nor based on scientific
evidence. However, there is a relatively small subset of women for whom HRT does
pose a potential health threat: those with a documented significantly increased risk of
breast cancer but without an increased risk of cardiovascular or other diseases that
can be prevented or delayed by the administration of postmenopausal estrogens.10
These women are more appropriately managed with nonestrogenic compounds. It is
the healthcare provider's obligation to perform an individualized HRT-related
risk-benefit assessment for every woman entering menopause. Subsequently,
through a provider–patient relationship, a regimen of lifestyle changes and nutritional
and pharmacologic interventions can be developed to maximize both quality and
length of life.
References
1.
Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol
1987;156:1332-4.
2.
Strickland DM, Hammond TL. Postmenopausal estrogen replacement in a large
gynecologic practice. Am J Gynecol Health 1988;2:26-31.
3.
Weiderpass E, Adami H-O, Baron JA, et al. Risk of endometrial cancer following
estrogen replacement with and without progestins. J Natl Cancer Inst
1991;91:1131-7.
4.
Feuer EJ, Wun LM, Boring CC, et al. The lifetime risk of developing breast
cancer. J Natl Cancer Inst 1993;85:892-7.
5.
U.S. Dept of Health and Human Services. Mortality, part B. In: Vital Statistics of
the United States: Various Years Through 1991. Hyattsville, Md: National Center
for Health Statistics; 1995:2.
6.
Bush TL, Whiteman MK. Hormone replacement therapy and risk of breast cancer
(editorial). JAMA 1999;281:2140-1.
7.
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;332:1589-93.
8.
Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal
estrogen and estrogen-progestin replacement therapy and breast cancer risk.
JAMA 2000;283:485-91.
9.
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;350:1047-59.
10.
Col NF, Eckman MH, Karas RH, et al. Patient-specific decisions about hormone
replacement therapy in postmenopausal women. JAMA 1997;277:1140-7.
11.
Garg PP, Kerlikowske K, Subak L, Grady D. Hormone replacement therapy and
the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet Gynecol
1998;92:472-9.
12.
Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer Statistics, 2000. CA
Cancer J Clin 2000;50:7-33.
13.
Newcomb PA, Storer BE. Postmenopausal hormone use and risk of large bowel
cancer. J Natl Cancer Inst 1995;87:1067-71.
14.
Potter JD. Hormones and colon cancer (editorial). J Natl Cancer Inst
1995;87:1039-40.
[Literature | Menopause Educational Materials | Conferences & Congresses | Opinion
Papers]
[News | Membership / Registration | Editorial Board | Web Links]
[About Women & Menopause | Home]