Hormone Replacement Therapy
What is an exogenous estrogen?
An endogenous estrogen is one that occurs naturally within the body. In contrast, an exogenous estrogen is one that comes from outside the body -- from a drug or from foods with estrogen-like properties. The exogenous estrogens used in birth control pills and estrogen replacement therapy may be manufactured from natural or synthetic sources. In the United States, the most common form of replacement estrogen is a natural estrogen called conjugated equine estrone (e.g., Premarin) -- "equine" because it is derived from the urine of pregnant mares. Some estrogen replacement drugs are made from plant estrogens (e.g., Ogen).
Does taking estrogen after menopause increase the risk of breast cancer?
Taking estrogen after menopause probably increases the risk of breast cancer, but not by a great deal. Because higher levels of endogenous (naturally occurring) estrogen are associated with a moderately increased risk of breast cancer, the same hormone taken as a prescription medication could be expected to act in a similar way. It is hard to be certain because the information about a connection between replacement estrogen and breast cancer is based on observational studies. In such studies, women choose whether or not to take estrogen, and then researchers observe them for a period of years to see whether the users get breast cancer more or less frequently than the nonusers.
A collaborative group of research scientists combined the data from 51 separate studies that included 160,000 women. The researchers calculated that each year of continuous use of hormone replacement therapy (HRT) was associated with a small increase in the risk of breast cancer. If 1,000 average 50-year-old women took HRT for five years and then stopped, there would be an additional two cases of breast cancer. For 10 years of continuous use, there would be six additional cases. For 15 years of continuous use, there would be an additional 12 cases per 1,000 women. These differences are important, but they are not extremely large. The extra risk applies while HRT is being taken; within five years after discontinuation of use, there is no extra risk when these women are compared with women who never used HRT.
This relatively small estimate of increased breast cancer risk is the best guess available for the time being. It is possible that the risk could be somewhat higher, somewhat lower, or not there at all. Some of the characteristics of women who choose HRT would make a breast cancer diagnosis more likely, even if HRT itself made no difference. These characteristics include smaller families, higher education, higher income, and more frequent use of breast screening. Other characteristics of women who choose HRT would make breast cancer less likely, even if HRT itself made no difference. These characteristics include lower weight, lower bone density, and a higher incidence of osteoporosis.
The bottom line is this: observational studies raise good questions, but they don't provide the answer. When results from the Women's Health Initiative trial are available in 2007, we will have a better idea about the connection between HRT and breast cancer, including whether or not a connection exists at all. This study is a large randomized controlled trial. Some of the participants in the trial were assigned to use HRT. Other identical women were assigned to use a placebo, a pill that looks like the HRT medication but contains no estrogen. If HRT makes a difference in the risk of breast cancer, this study and similar ones in Europe will be able to tell how much that difference is.
Finding a good answer in 2007 is not a lot of help for the menopausal woman right now. She needs to know if the possible long-term risk from HRT outweighs the definite short-term benefit from control of the symptoms of menopause. The best guess is that any potential increased risk of breast cancer from short-term use of HRT is so small that there is no way to distinguish it from "no difference at all." Large differences in risk are easy to spot. If there were a large and significant increase in the risk of breast cancer from short-term use of HRT, it would certainly have been noticed and measured by now.
Does taking estrogen after menopause increase the risk of other cancers?
If taken alone, postmenopausal estrogen increases the risk of other cancers. Estrogen stimulates cell growth in the lining of the uterus. Endometrial (uterine) cancer is four to five times more common among women who use estrogen replacement therapy than in women who do not. As a comparison, the 10-year risk of breast cancer for an average 50-year-old woman is 2.7%. The 10-year risk of endometrial cancer for the same woman is 0.6%. The use of estrogen alone would increase the risk of endometrial cancer to that of breast cancer. That is why the hormone progesterone is prescribed along with estrogen (combined HRT) whenever a woman has an intact uterus (that is, when she has not had a hysterectomy). Progesterone counteracts the effect of estrogen on the lining of the uterus. Combined HRT does not increase the risk of endometrial cancer, whereas unopposed estrogen (estrogen without progesterone) does increase the risk.
Does taking estrogen after menopause reduce the risk of heart disease?
It is not probable that postmenopausal estrogen reduces the risk of heart disease (combined HRT may even increase the risk), even though in dozens of observational studies, women who chose to take HRT developed heart disease, or died from heart disease, around 25–50% less frequently than women who did not choose to take HRT. As in the studies of breast cancer, the women who volunteered for HRT were different from those who did not volunteer. They were different in ways that made heart disease less likely -- fewer smokers, lower blood pressure, lower cholesterol, and lower weight. The difference in heart disease rates could have been due to these and other factors, rather than to HRT.
Several randomized controlled trials of estrogen therapy for women with a previous history of heart disease have already been completed. In each study, the women randomly assigned to receive HRT had at least as many new heart attacks, fatal heart attacks, or coronary bypass surgeries as the women who did not receive HRT. The possible long-term effect of HRT on the risk of heart disease for women with no current heart problems is unknown. Tentative data, based on the frequency of cardiovascular disease among women in 22 randomized trials conducted for other purposes, do not suggest that HRT provides a protective effect. The risk of heart disease is not connected to levels of endogenous (naturally occurring) estrogen, so there is no particular reason to expect that estrogen in a prescription medication would act differently.
The uncertainty about the role of HRT in influencing the risk of heart disease is an important reason for women to watch -- and perhaps to participate in -- randomized trials designed to find out which health behaviors, preventive services, or medications can make a real difference in the health of women. Hormone replacement therapy has been available for over 50 years as a highly effective treatment for hot flashes and other symptoms of menopause. Complex and expensive randomized trials could determine if long-term use of HRT has an effect -- in one direction or another -- on the risk of heart disease, breast cancer, and other aspects of women's health. From the 1950s through the 1980s, no study of this nature was proposed or funded. In 1991, under the leadership of its first female director, the National Institutes of Health launched the Women's Health Initiative, a large, long-term, randomized, controlled trial that could finally answer the questions.
