Continuing Quandaries about Hormone Replacement Therapy
A study published in the November issue of the American Journal of Epidemiology adds to the substantial body of research suggesting caution for postmenopausal women considering the use of hormone replacement therapy, particularly when it includes the hormone progestin.
Harvard researchers Drs. Graham Colditz and Bernard Rosner evaluated 14 years of data from 58,520 women participating in the ongoing Nurses Health Study. They found that the use of estrogen therapy by women from ages 50 to 60 increased their cumulative risk of breast cancer at age 70 by 23 percent compared with women who had never used hormones. However, the risk was increased by 67 percent in those who used estrogen plus progestin.
They found that alcohol use increased the cumulative risk by 7 percent in women who reported one alcoholic drink per day from age 18 years. Other well-known risk factors, such as a family history of breast cancer, age at menopause, and age at first period, also affected the cumulative risk. Surprisingly, the researchers also found that the cumulative risk of breast cancer at age 70 was increased by 57 percent in women with a history of benign breast disease.
The above study further reinforces the conclusions of a bevy of reports issued over the past few years that have consistently warned women to weigh the benefits versus risks of hormone replacement therapy, especially so-called combination therapy which includes progestin in addition to estrogen.
Estrogen is a hormone produced primarily by the ovaries. It aids in developing female sex organs and in regulating monthly menstrual cycles. Progesterone is a hormone that is released by the ovaries during every menstrual cycle and helps prepare a woman's body for pregnancy. After a woman goes through menopause, her production of these hormones is drastically reduced. In the short-term, hot flashes, bone loss, vaginal dryness and mood swings can occur. In the long-term, a woman faces a greater risk of osteoporosis and heart disease.
Hormone replacement therapy-often referred to as HRT-is used to replace these hormones not being produced after menopause. It can significantly reduce a woman's risk of osteoporosis and heart disease. While developing breast cancer is a top concern among many women, more than 10 times as many women die from cardiovascular disease.
And yet, exposure to hormones is thought to increase a woman's risk of developing breast cancer. Since HRT adds estrogen (and often progesterone) back to the body, many studies have looked for a possible link between the use of HRT and breast cancer.
Although it still has not been proven that estrogen causes breast cancer, estrogen may help some breast cancer cells grow when the tumor is already present in a woman's body. Therefore, once a woman is diagnosed with breast cancer, tests are done to see if her cancer is positive for estrogen and progesterone receptors. These receptors are the parts of a cancer cell that attract estrogen or progesterone.
If the cancer is found to have these receptors, hormones flowing in the body can attach themselves to breast cancer cells and help those cells grow and multiply. In these cases, therapies such as tamoxifen are used to prevent hormones from attaching to the cancer cells.
Women need to consider their personal risks for osteoporosis and heart disease, in addition to their personal risk for breast cancer, when making decisions about hormone replacement therapy.
For an average women at low risk for breast cancer, or one who is at an increased risk for cardiovascular disease or osteoporosis, the small increased risk of breast cancer associated with long-term hormone replacement therapy may be worth it to her.
Conversely, for some women at an increased risk for breast cancer due to advancing age, a strong family history, or premalignant biopsies, the risks of hormone replacement therapy may outweigh the benefits.
It seems as if there is significantly more risk associated with combination hormone replacement therapy that includes progestin, as opposed to just using estrogen replacement therapy (ERT).
For example, a study published by University of Southern California researchers in the Journal of the National Cancer Institute found that the addition of progestin to a woman's hormone replacement therapy substantially increases her risk of developing breast cancer relative to the use of estrogen alone.
A research team led by Dr. Ronald Ross compared 1,897 postmenopausal women with breast cancer with 1,637 postmenopausal women without the disease. Hormone replacement therapy was used by just over half of the breast cancer patients (54 percent) and control subjects (52 percent). Most patients used "unopposed" estrogen replacement therapy (ERT), as compared to combination therapy that included progestin.
The researchers found that using ERT alone increased the risk of breast cancer only in women who took estrogen for 15 years or more. However, adding progestins to the HRT regimen substantially increased the breast cancer risk. Five years of such combination therapy increased a woman's risk of breast cancer by 24 percent-four times as much as ERT.
The increased risk of using only ERT was limited to in situ disease, the researchers found. But the risk associated with combination HRT was apparent for all stages of breast cancer.
"This study," the authors wrote, "provides the strongest evidence to date that progestins not only do not protect the breast from the carcinogenic effects of estrogen, but also increase substantially the small ERT-related increase in breast cancer."
Another study, by Dr. Christopher Li of the Fred Hutchinson Cancer Research Center in Seattle and colleagues, concluded that the increased risk of breast cancer associated with the use of combined hormone replacement therapy appeared to be limited to an increase in the incidence of lobular tumors in women over age 50. The researchers did not detect an increase in the risk of ductal breast cancer in these women.
Lobular tumors represent only 5 - 10 percent of all cases of breast cancer.
Writing in the journal Cancer, Li's team interviewed white women with invasive or in situ breast cancer who were between 50 and 64 years of age at the time of diagnosis. Fifty-eight women had lobular disease and 370 had ductal disease. A group of 492 age-matched women without a diagnosis of breast cancer served as controls.
Among women who had previously used hormone replacement therapy with estrogen and progestin for at least 6 months, the relative risk of lobular breast cancer was 2.1 compared with those who had never used HRT, they wrote. Among the current HRT users, the relative risk was 2.6.
However, women who used only estrogen replacement therapy (ERT) but never combined hormone replacement therapy had only a slightly increased risk of lobular breast cancer that was "well within the limits of chance," they wrote. The risk of ductal carcinoma was not elevated by either estrogen-only or combination hormone therapy.
In response to studies such as these, the American Association of Clinical Endocrinologists (AACE), the American Medical Women's Association, and other healthcare groups have issued statements cautioning women not to abandon hormone replacement therapy without first talking with their doctors.
For example, the AACE notes that many studies using different methods have not shown the same increase in breast cancer risk associated with hormone replacement therapy. Furthermore, the lower-dose progestin frequently used today in combination HRT has not been associated with as high a risk for breast cancer.
They further point out that, "For each case of breast cancer due to long-term estrogen use, more than 6 deaths from heart disease are prevented, and overall mortality is substantially reduced in women using HRT."
Any woman who is considering starting, changing or stopping hormone replacement therapy should first talk with her doctor. The severity of her menopausal symptoms, and her risk factors for cardiovascular disease, osteoporosis and breast cancer should all be carefully weighed in the decision.
SOURCES:
American Journal of Epidemiology, November 2000; 152:950-964
Cancer, June 2000; 88:2561-2577
Journal of the National Cancer Institute, February 16, 2000; 92:328-332
American Association of Clinical Endocrinologists (http://www.aace.com)
The Susan. G. Komen Breast Cancer Foundation (http://www.komen.org)
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