Feb. 4, 2000 Study of Los Angeles women shows one type of progestin and estrogen therapy poses greatest risk
Hormone replacement increases the risk of breast cancer in postmenopausal women, according to results of a study by University of Southern California researchers published in the Feb. 16 issue of the Journal of the National Cancer Institute. The study found that although estrogen has long been considered the primary hormonal risk, progestin may be a more important factor.
Ronald K. Ross, M.D., professor of preventive medicine at the USC Keck School of Medicine, and colleagues at the USC/Norris Comprehensive Cancer Center found that for every five years a woman uses estrogen, the risk of breast cancer increases six percent. But for every five years a woman takes both estrogen and progestin, called combined therapy-today's standard hormone replacement therapy to ease the symptoms of menopause-the risk of breast cancer rises 24 percent, the researchers showed.
Researchers often study hormone replacement therapy's effects, but this is by far the largest study to examine the effects of estrogen and progestin as well as estrogen alone on breast cancer. The study has more data than the combined world literature on this subject, including the recent National Cancer Institute study showing a link between hormone replacement therapy and breast cancer.
The USC researchers conducted a study of 1,897 postmenopausal women in Los Angeles County who were diagnosed with breast cancer in the late 1980s and mid-1990s, and compared them to 1,637 similar women with no breast cancer. The women, identified through the county's population-based cancer registry (the Cancer Surveillance Program, which Ross directs), were asked about their history of hormone replacement therapy and oral contraceptive use. The study included significant numbers of long-term hormone replacement therapy users who were found to have breast cancer. (The study found that for women who used combination therapy for 10 years or more, the risk of breast cancer was 50 percent greater compared to non-users of hormone replacement therapy). Doctors have prescribed estrogen to postmenopausal women to prevent osteoporosis, and the hormone markedly decreases the incidence of cardiovascular disease, the No. 1 cause of death in the United States, a finding first reported by this group of USC investigators. But using estrogen alone has been shown to substantially increase a woman's risk of endometrial cancer (also known as uterine cancer), the most common gynecological cancer. In response, medical scientists in the mid-1970s introduced the combined therapy of estrogen and progestin to reduce that danger-but no one was sure how combined therapy would affect the risk of breast cancer.
A woman can take combined therapy in two ways. One is called continuous combined therapy, in which she takes both estrogen and progestin every day of the month. The other is called sequential estrogen and estrogen plus progestin therapy, in which she takes estrogen alone during part of a month and then both estrogen and progestin during the rest of the month.
The researchers found that risks were higher for women who were on the sequential therapy than the continuous therapy (with breast cancer risk increasing 38 percent every five years for the sequential therapy users, far higher than the 9 percent risk increase every five years for the continuous therapy users). Although the differences were not statistically significant in the study, Ross says, the differences in risk were consistent among all segments of women studied and have implications for how hormone replacement therapy is best administered.
"Continuous combined therapy may be better overall, since you tend to see lower doses of progestin in that therapy," says Ross, who holds the Catherine and Joseph Aresty Chair in Urologic Research at the Keck School of Medicine of USC. Over time, he says, the doses of hormone administered to postmenopausal women might be lowered to decrease disease risk, much like the trend toward lower-dose birth control pills.
Progestin's biological effects on the breast are not extensively known, but they appear to support the results of the study, the authors note. The function of the body's natural version of the hormone, progesterone, is to prepare a woman's uterus to support a fertilized egg. Its levels in the body fluctuate during a woman's menstrual cycle, reaching its peak about a week before menstruation-at the same time that cells in the breast are dividing and reproducing most actively.
Cancer is the defective and uncontrollable division and reproduction of cells, the result of an accumulation of genetic misfirings whose intricacies are still under study. "The underlying premise is that anything that increases cell divisions in a certain organ increases the likelihood that cells in that organ become cancerous," Ross says.
The behavior in the breast contrasts with the hormone's behavior in the uterus, where progesterone actually inhibits cells from dividing and reproducing. That might explain why using combined progestin and estrogen therapy results in a lower risk of endometrial cancer than use of unopposed estrogen therapy.
The study authors concluded that the benefits of estrogen alone outweigh its risks. For each case of breast cancer in women due to long-term estrogen use, more than six deaths from heart disease are prevented, they write. Similar data to balance the benefits and risks of combined therapy are unavailable; but if the main reason for prescribing combined therapy instead of unopposed therapy is to protect a woman from endometrial cancer, they write, "then this study would argue that the adverse effect on the breast may outweigh the beneficial effect on the endometrium, at least in terms of cancer morbidity and mortality."
In the United States, recent population statistics show that 110 of every 100,000 women develop breast cancer annually. This is five times greater than the rate of endometrial cancer, which is 21 cases in every 100,000 women. Women also are more likely to die from breast cancer than from endometrial cancer.
Ross says the researchers hope to look into how breast cancer risk differs among women on hormone replacement therapy with different characteristics, such as family history of breast cancer, history of benign breast disease and exercise. They also hope to look at whether the increased risks from hormone replacement therapy are more likely to be in those expressing estrogen and progestin receptors. (Receptor-positive tumors need estrogen or progestin to grow and, overall, tend to respond better to certain treatments).
The authors concluded that doctors should provide women with information about the possible effects of hormone replacement therapy, and women should be told where uncertainty still remains in weighing risks against benefits.
EDITOR: See Ronald K. Ross, Annlia Paganini-Hill, Peggy C. Wan and Malcolm C. Pike, "Effect of Hormone Replacement Therapy on Breast Cancer Risk," Journal of the National Cancer Institute, Vol. 92, No. 4.
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