New Breast Cancer Risk Found With Hormone Replacement Therapy
Hormone Combination Found Riskiest; Experts Advise Short-Term Use Only
By Theresa Defino
Jan. 25, 2000 (Washington) -- Using estrogen combined with progesterone for hormone replacement therapy (HRT) for more than a few years increases a woman's risk of breast cancer far beyond what she would experience without the therapy, according to the largest study of the association between breast cancer and HRT. The lead investigator on the research, conducted by the National Cancer Institute, says the data call for a re-examination of long-term HRT use, but experts who reviewed the research for WebMD caution against overemphasizing the findings.
The concentrations of estrogen and progesterone, the two main female sex hormones, fall as women go through menopause. This decrease can lead to many adverse symptoms, some possibly life threatening and others that are less serious but troublesome and affect a woman's quality of life. The most common are hot flashes, vaginal dryness, bone loss leading to osteoporosis and fractures, and an increase in heart disease, partially due to a rise in cholesterol levels.
It is estimated that some 20% or more of women over the age of 45 take HRT, which can be in the form of estrogen alone or in combination with progesterone. The benefit of HRT is derived mainly from the effects that estrogen has on the body. However, taking estrogen alone is associated with a fivefold increase in the risk of cancer of the uterus, and thus progesterone must also be taken in women who have not had a hysterectomy.
HRT can be taken for several years or less to relieve the menopausal symptoms, but many women also stay on it for years for a variety of reasons, including the belief many physicians have that it protects women against heart disease and osteoporosis. Some preliminary research also suggests a lack of estrogen may play a role in Alzheimer's disease. Some women also report depression and anxiety and find relief with HRT.
The study, reported in the Jan. 26 Journal of the American Medical Association, involved over 46,000 women. Compared with women who received no hormone therapy, women who took estrogen and progesterone in combination for an average of 3.5 years had a 40% greater chance of developing breast cancer, and those who used estrogen alone for an average of 10 years had a 20% higher risk of breast cancer.
The risks were also calculated by each increasing year of use. Women on estrogen alone had an increased risk of 1% a year for each year of use, compared with women on the estrogen-progesterone combination, for whom the increase was 8% a year. The ill effects were seen most in women with long-term use, and the increased risk seemed to disappear within four years after HRT has been stopped.
Lead author Catherine Schairer, PhD, an epidemiologist with the National Cancer Institute, tells WebMD she does not support completely abandoning long-term HRT based on her research. "I think one study is never definitive. There need to be other studies confirming these results. On the other hand, I feel reasonably confident of my results. I think a woman may still consider the use of estrogen alone if she has a uterus. If a woman still feels she wants HRT, she should be carefully monitored. She should at least get what is recommended in terms mammograms and clinical exams."
While Walter Willett, MD, DrPH, and his colleagues at the department of epidemiology and nutrition at the Harvard School of Public Health call "strong" the "evidence that the addition of progesterone to estrogen increases the risk of breast cancer," they write in an accompanying editorial that the cause-and-effect remains unproven. Still, they urge a pointed review of the reasons why menopausal women would be placed on hormone therapy, and they admonish clinicians and patients for overlooking lifestyle interventions.
Felicia Cosman, MD, urges a measured response to the research.
"I think it would be a mistake for women who are taking estrogen to stop taking it based on this study," Cosman says. "Women should not indiscriminately go on estrogen because they go through menopause. If they and their doctors feel that the heart disease data and the osteoporosis data and the preventive effects for Alzheimer's disease data are strong, and they have a history of those diseases, then I think it is reasonable" to be on HRT long-term. Cosman, who is clinical director for the National Osteoporosis Foundation and an endocrinologist and director of osteoporosis programs at Helen Hayes Hospital in New York, reviewed the study for WebMD.
"What I don't like, and I see this every day, is women who've been on estrogen for years for no specific reason," Cosman says. "I ask them why, and they say, 'I don't know, my doctor put me on it.' The conclusion is that we all should have a reason for being on hormones. And if we take them, we should be on the lowest possible dose of [progesterone]."
Schairer and her colleagues stop short of offering guidelines for HRT use, but Willett and his colleagues at Harvard attempt to sort out this controversial and perplexing issue. They write that short term use to quell menopausal symptoms, with a two to three-year course of treatment, "should not be influenced by fear of cancer risks." Secondly, for women without a uterus, the combination therapy is unwarranted anyway, because there is no need for the progesterone and its beneficial effects on the uterus.
But for the third group of menopausal women with a uterus, who comprise the vast majority of HRT users, the questions of benefit vs. risk doesn't have such tidy answers. "[R]educing the risks of fractures and heart disease will rarely provide sufficient justification because avoidance of smoking, performance of regular exercise, and consuming a good diet are effective preventive measures," they write. They point out that there are many new medications that can be used for heart disease and osteoporosis prevention that were not available in the past.
"The commonly held belief that aging routinely requires pharmacological management has unfortunately led to neglect of diet and lifestyle as the primary means to achieve healthy aging," they write. "Now is an appropriate time to reassess this emphasis."
Cosman says the decision to stop -- or start HRT -- isn't easy. "I have to tell you that I have patients who've been on long term estrogens who don't want to change. They think they look better, they feel better, the skin is better, the hair is better. Although this isn't true disease prevention, it probably is a quality of life issue that has to be considered with some women."
Eugenia Calle, PhD, director of analytical epidemiology at the American Cancer Society, reviewed the study for WebMD and says it appears that the risk of breast cancer with HRT with progesterone is greater than first believed. But she adds that the findings are not surprising. "It really does look like from these data that if women continue to use these combination products for a longer period of time, the risks may turn out to be moderate and less modest," says Calle. "We've been heading in this direction, and we've known of the association between breast cancer and combination therapy ... that is not brand new, it's what we suspected. The main contribution of this study is it gives us a more precise amount of risk that a woman may incur if they use the combination product for a number of years."
But she adds, "This is one study and there will be others looking that this." The risk should also be put in perspective. Calle notes, for example, that people who smoke are 20 to 25 times more likely to develop lung cancer than are nonsmokers, while women on the combination HRT product were less than two times as likely to develop breast cancer than were estrogen-alone users and women who have never used estrogen products.