The controversies regarding the association between hormonal replacement
therapy (HRT) and cancers, the questions about HRT use in women with a
high risk of breast cancer, and the increasing number of women with breast
cancer and menopausal symptoms make HRT a significant cancer issue.
The scope is immense and growing as the baby boom generation approaches
menopause. Currently, more than 30 million woman are postmenopausal, and
the average life expectancy after menopause is 30 years. Despite the
well-recognized benefits of HRT with regards to heart disease and osteoporosis,
concern about the risk of cancer seems to prevent some physicians from
prescribing HRT and many patients from using HRT.
Since the 1930s, physicians have known that estrogen therapy reduces
menopausal symptoms. The 1960s saw a dramatic increase in the number of
women using estrogen. The number of prescriptions for estrogen decreased
from 1975 to 1980 because of reports of an association of unopposed estrogen
and endometrial cancer, and then increased through the mid-1980s.
Despite findings in the late 1980s and 1990s that estrogen reduces the
risk of osteoporosis, heart disease, and Alzhei-mer's dementia, many women
still are reluctant to take estrogen because of fear of endometrial and
As with any medication, the benefits of symptom relief and disease prevention
must be weighed against the risks or side effects. If women are to make
such decisions about HRT based on evidence rather than fear, they need
a clear understanding of their individual risks and benefits.
Women opt to use HRT to alleviate menopausal symptoms, reduce their
risk of heart disease and/or osteoporosis, or as part of a treatment plan
for recently diagnosed heart disease. Alternatively, women may choose not
to use HRT due to cost, physician advice, unwanted side effects, withdrawal
bleeding, inconvenience, and fear of the risks, especially the risk of
Surveys on women's attitudes and knowledge regarding HRT use suggest
that they know more about potential risks, such as breast cancer, than
about proven benefits, such as preventing osteo-porosis and heart disease.[6-8]
Consequently, they may give more weight to potential cancer risks than
Endometrial cancer is not very common. A metaanalysis of studies that
examined the association between unopposed estrogen and endometrial cancer
found a summary relative risk of 2.3 (CI 2.1 to 2.5), comparing the risk
of endometrial cancer in women who took unopposed estrogen at any time
with those who never took estrogen.
Both increasing the dose and duration of unopposed estrogen therapy
further increases the risk of endometrial cancer. Most women who develop
endometrial cancer on HRT can be treated effectively with a hysterectomy.
To avoid the increased risk of endo-metrial cancer, women with a uterus
should be treated with either cyclic or continuous progestin.
There is significant controversy in the literature about HRT as a risk
for breast cancer. The most recent studies do not suggest a significant
increase in the risk of breast cancer with the current estrogen and progestin
Studies consistently find no excess risk of breast cancer associated
with relatively short-term (less than five years) HRT use. Exceptions
to this include long-term HRT users and individuals already at an increased
risk because of a family history of breast cancer.
HRT may protect women from colon cancer. Several studies have shown
that HRT use is associated with a lower risk of colon cancer. Most
recently, Newcomb et al found HRT use was associated with a significant
reduction (about 30% for ever use and 46% for recent use) in colon cancer
This inverse association with risk for colon cancer was observed among
users of both estrogen only and estrogen and progestin combination therapy,
and was maintained for at least 10 years after stopping HRT use.
HRT for Cancer Survivors
A contraindication to HRT is an estrogen-dependent neoplasia; however,
stage I endometrial cancer is not a contra-indication. Creasman et
al found that patients with stage I endometrial cancer treated with estrogen
survived longer than those patients who were not treated with estrogen.
Lee et al treated patients with endometrial cancer (low-grade lesions,
less than 50% local invasion, and without nodal metastasis) with estrogen.
In five years of follow-up, no recurrence of endometrial cancer was identified
in the treatment group, and a higher mortality was observed in the control
group from cardiovascular disease.
Guidelines for the use of estrogen therapy in endometrial cancer survivors
have been proposed:
- Estrogen-receptor (ER) and progesterone-receptor (PR) status of the
tumor should be determined at the time of surgical staging.
- Patients who are found to be at low risk for cancer recurrence may
begin taking estrogen therapy.
- Patients who are found to be at high risk for cancer recurrence but
who are ER negative may begin estrogen therapy.
- Patients who are found to be at high risk for recurrence and are ER
positive are to be monitored for a three- to five-year disease-free interval
prior to initiating estrogen therapy.
Many women are surviving breast cancer, and a large proportion of women
who are premenopausal when breast cancer is diagnosed develop chemotherapy-induced
menopause. Although having a history of breast cancer is a relative
contraindication to HRT, some physicians prescribe HRT for survivors of
breast cancer, especially those with severe menopausal symptoms.
A few studies have looked at the impact of HRT in breast cancer survivors.[19-21]
The most recent study from Australia found no deaths and significantly
fewer recurrences in patients who were given continuous estrogen-proges-terone,
compared with controls (despite the high doses of progestin, 10 to 20 times
higher than used in the United States).
While the definitive prospective studies to show that HRT is safe in
survivors of breast cancer are still needed, the risks and benefits of
HRT should be discussed.
Informed Decision Making
Counseling patients about the benefits and risks of HRT is a complex
process made particularly difficult by the need for probabilistic thinking,
with which many patients are neither familiar nor comfortable. Nevertheless,
patients want to be and should be involved in the decision-making process.
Patient involvement is particularly important when the decision involves
an intervention in asymptomatic patients, ie, when HRT is used for long-term
benefits. Patients need to have the critical facts to make these decisions,
but many physicians may not be aware of the risks and benefits of HRT.
|Core Information Patients Need to Make Informed Decisions About
Hormone Replacement Therapy
Women's Health Initiative
Although controversy exists with regards to the benefits and risks of
HRT, the Women's Health Initiative sponsored by NIH, has been designed
to test many of these effects. The primary outcomes to be studied are cardiovascular
disease, breast cancer, colorectal cancer, and osteoporotic fractures.
The interventions include a trial of HRT, a trial of a low-fat diet
to prevent breast and colon cancer, and a trial of calcium and vitamin
D to prevent osteo-porotic fractures. The answers to the primary design
questions will be available by the year 2007.
Many questions about HRT in cancer patients remain unanswered, and more
research is needed to address questions in the following areas:
- The effects of HRT from randomized trials that eliminate the problems
of selection bias.
- The effects of HRT in specific subgroups, ie, women with known family
history of breast cancer or the BRCA1 or BRCA2 cancer genes.
- The effects of HRT using continuous versus cyclic progestin therapy
or other progesterone compounds.
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