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Menopausal Hormone Use and Cancer
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Submitted By: Information, News and Press Releases
Source: National Cancer Institute Fact Sheet (www.cancer.gov)Reviewed: 05/04/2006
Menopausal Hormone Use and Cancer: Questions and Answers
What is menopause?
Menopause is the time in a woman’s life when menstruation ends. It is part of a biological process that begins, for most women, in their mid-thirties. During this time, the ovaries gradually produce lower levels of natural sex hormones—estrogen and progesterone. Estrogen promotes the normal development of a woman’s breasts and uterus, controls the cycle of ovulation (when an ovary releases an egg into a fallopian tube), and affects many aspects of a woman’s physical and emotional health. Progesterone controls menstruation (having a period) and prepares the lining of the uterus to receive the fertilized egg.
“Natural menopause” occurs when a woman has her last menstrual period, or stops menstruating, and is considered complete when menstruation has stopped for 1 year. This usually occurs between ages 45 and 55, with variations in timing from woman to woman. Women who undergo surgery to remove both ovaries (an operation called bilateral oophorectomy) experience “surgical menopause”—an immediate end to menstruation caused by lack of hormones produced by the ovaries.
By the time a woman has reached natural menopause, estrogen output has decreased significantly. Even though low levels of this hormone are produced by other organs after menopause, they are only about one-tenth of the level found in premenopausal women. Progesterone is nearly absent in menopausal women.
What are menopausal hormones and why are they used?
Doctors may recommend menopausal hormones to counter some of the problems often associated with the onset of menopause (hot flashes, night sweats, sleeplessness, and vaginal dryness) or to prevent some long-term conditions that are more common in postmenopausal women, such as osteoporosis. Menopausal hormone use (sometimes referred to as hormone replacement therapy or postmenopausal hormone use) usually involves treatment with either estrogen alone or estrogen in combination with progesterone or progestin, a synthetic hormone with effects similar to those of progesterone. Among women who are prescribed menopausal hormones, women who have undergone a hysterectomy (surgery to remove the uterus and, sometimes, the cervix) are generally given estrogen alone. Women who have not undergone this surgery are given estrogen plus progestin, which is known to have a lower risk of causing endometrial cancer (cancer of the lining of the uterus).
How does medical research determine the benefits and risks of taking menopausal hormones?
Researchers commonly conduct two very different, yet important types of studies with people to examine the benefits and risks of hormone use: clinical trials and observational studies. In clinical trials, the participants are given either hormones or placebos (look-alike pills that do not contain any drug) to determine the effect of the hormones on various conditions and diseases. In observational studies, the investigators do not try to affect the outcome; they compare the health status of women taking hormones to women not taking hormones. The strongest evidence for proving an association between menopausal hormones and a disease or condition comes from clinical trials.
What has medical research found out about the risks and benefits of hormone use after menopause?
The most comprehensive evidence about the risks and benefits of taking menopausal hormones to prevent disease after menopause comes from the Women’s Health Initiative (WHI) Hormone Program, which was sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI), parts of the National Institutes of Health (NIH). This research program examined the effects of menopausal hormones on women’s health. The WHI Hormone Program involved two studies—the use of estrogen plus progestin for women with a uterus (the Estrogen-plus-Progestin study), and the use of estrogen alone for women without a uterus (the Estrogen-Alone study). In both hormone therapy studies, women were randomly assigned to receive either the hormone medication being studied or the placebo.
The WHI Estrogen-plus-Progestin study was stopped in July 2002, when investigators reported that the overall risks of estrogen plus progestin, specifically Prempro™, outweighed the benefits (1) . The researchers found that use of this estrogen plus progestin pill increased the risk of heart disease, stroke, and blood clots, as well as breast cancer. The findings also showed fewer cases of colorectal cancer among women using estrogen plus progestin than among those taking the placebo (1).
The WHI Estrogen-Alone study, which involved Premarin™, was stopped in February 2004, when the researchers concluded that estrogen alone increased the risk of stroke and blood clots. In contrast with the WHI Estrogen-plus-Progestin study, the use of estrogen alone had no significant effect on the risk of breast or colorectal cancer (2).
How does menopausal hormone use affect breast cancer risk and survival?
The WHI Estrogen-plus-Progestin study concluded that combination therapy increases the risk of invasive breast cancer. After 5 years of follow-up, women taking these hormones had a 26 percent increase in breast cancer risk compared with women taking the placebo. The increase amounted to an additional 8 cases of breast cancer for every 10,000 women taking estrogen plus progestin for 1 year compared with 10,000 nonusers (1).
A more detailed analysis showed that, among women taking estrogen plus progestin, the breast cancers were slightly larger and diagnosed at more advanced stages compared with breast cancers in women taking the placebo. Among women taking these hormones, 25.4 percent of the cancers had spread outside the breast to nearby organs or lymph nodes compared with 16.0 percent among nonusers (3). Breast cancer that has spread to other parts of the body (metastatic breast cancer) is more difficult to treat. Earlier studies had suggested that, although estrogen plus progestin increased risk, the breast cancers that were diagnosed in women taking the combination had features associated with good prognoses (likelihood of recovery). The WHI Estrogen-plus-Progestin study showed that not to be the case.
The WHI Estrogen-Alone study did not find a significant increase in the risk of breast cancer in women with a prior hysterectomy during the 7 years the study was conducted. Initial results suggested that the incidence of breast cancer was lower in the estrogen group than in the placebo group (2). In a more recent analysis, researchers concluded that the lower incidence was not significant; i.e., it was less than what might be expected to happen by chance alone (4).
Among the general population of postmenopausal women, observational data have shown that hormone use is associated with an increased risk of breast cancer, with the greatest risk among women using estrogen plus progestin (5, 6, 7). In the Million Women Study, which was published in 2003, British researchers found that current use of estrogen, estrogen plus progestin, or other hormone preparations significantly increased the risk of breast cancer in women ages 50 to 64. Women using estrogen plus progestin were at greater risk than those using other hormone preparations. Current hormone users were also more likely to die from breast cancer than women who did not use them. Within about 5 years of stopping use, increased risk largely disappeared for women who took estrogen alone (5).
What are the effects of hormone use on the risk of endometrial cancer?
Studies have shown that long-term exposure of the uterus to estrogen alone increases a woman’s risk of endometrial cancer. The risk associated with estrogen plus progestin appears to be much less, but some data suggest that the risk is still increased compared with nonusers. The long-term effects of estrogen plus progestin on endometrial cancer risk remain uncertain (8).
The WHI Hormone Program showed that endometrial cancer rates for women taking estrogen plus progestin daily were the same as or possibly less than those for women taking the placebo pill. Uterine bleeding, however, was a common side effect, leading to more frequent biopsies and ultrasounds for women taking combined hormones compared with those taking a placebo (9).
The Million Women Study confirmed a lower risk of endometrial cancer in women taking combined hormones compared with those taking estrogen only or tibolone, a synthetic steroid that is not available in the United States (10). More studies are needed to assess the effects of estrogen plus progestin on endometrial cancer.
How does menopausal hormone use affect the risk of ovarian cancer?
Several observational studies have found that the use of estrogen alone is associated with a slightly increased risk of ovarian cancer for women who used this hormone for 10 or more years. One observational study that followed 44,241 menopausal women for approximately 20 years concluded that women who used estrogen alone for 10 or more years were twice as likely to develop ovarian cancer compared with women who did not use menopausal hormones (11). Another large observational study also found an association between estrogen use and death due to ovarian cancer. In this study, the increased risk appeared to be limited to women who used estrogen for 10 or more years (12).
Data from the WHI Estrogen-plus-Progestin study indicate that there may be an increased risk of ovarian cancer with combined hormone use (9). After 5.6 years of follow-up, a 58 percent increased risk of ovarian cancer was reported in women using estrogen plus progestin compared with nonusers, but the increased risk was not statistically significant. One observational study suggested that combined estrogen-progestin regimens do not increase the risk of ovarian cancer if progestin is used for more than 15 days per month (13), but this study was too small to draw firm conclusions. More research is needed to clarify the relationship between menopausal hormone use, particularly for combined therapy, and the risk of ovarian cancer.
How does menopausal hormone use affect the risk of colorectal cancer?
After 5 years of follow-up of women taking estrogen plus progestin, the WHI Estrogen-plus-Progestin study reported a 37 percent reduction in colorectal cancer cases compared with women taking the placebo (1). On average, the researchers found that if a group of 10,000 women takes estrogen plus progestin for a year, 6 fewer cases of colon cancer will occur than in nonusers. The WHI Estrogen-Alone study concluded that estrogen alone had no significant effect on colorectal cancer risk (2). However, these data are not consistent with those from observational studies. More research is needed.
What are the risks of menopausal hormones for women who have a history of cancer?
One of the roles of naturally occurring estrogen is to promote the normal growth of cells in the breast and uterus. For this reason, there is concern that menopausal estrogen use by women who have had cancer may promote further tumor growth. The U.S. Food and Drug Administration (FDA) advises women with a history of cancer not to take menopausal hormones containing estrogen and progestin. The effect of menopausal estrogen use after endometrial and breast cancer remains uncertain (14). Little research has been done on the risks associated with menopausal hormone use by women who have had endometrial cancer. A few small studies have found no evidence that hormone use has a negative effect on survival and/or recurrence of the disease in these women (15). However, no large, long-term studies have compared the potential benefits, such as protection against osteoporosis, with the potential cancer risks.
One observational study of breast cancer patients, most of whom were using estrogen alone, reported no increase in recurrence or mortality among women who continued hormone use after their diagnosis (16). Another study of breast cancer patients showed that users of estrogen had lower mortality rates from breast cancer than patients who did not use estrogen. Most of these patients stopped using estrogen at the time of diagnosis. However, the benefit of prior estrogen use diminished with time (17).
Does the way in which hormones are administered make a difference?
Most of the data on the long-term health effects of hormones come from studies in which hormones (estrogen alone or estrogen in combination with progesterone or progestin) are administered orally in the form of pills. Other ways hormones are given include transdermal patches, gels, and vaginal creams and rings. These forms of estrogen are all equally effective methods of treating menopause-related problems, such as hot flashes and vaginal dryness. Progesterone is also available as a pill or gel.
The amount of estrogen that enters the bloodstream from estrogen-containing vaginal creams and rings depends on the types of hormones and the dose. Generally, vaginal administration of hormones results in lower levels of circulating hormones compared with an equivalent oral dose. Because the vaginal epithelium (thin layer of tissue that covers the vagina) responds to very small doses of estrogen, low-dose estrogen-containing creams can be used to correct some effects of menopause on the vagina.
What should women do if they are concerned about taking menopausal hormones?
Although menopausal hormones have short-term benefits such as relief from hot flashes and vaginal dryness, several health concerns are associated with their use. Women should discuss with their health care provider whether to take menopausal hormones and what alternatives may be appropriate for them. The FDA currently advises women to use menopausal hormones for the shortest time and at the lowest dose possible to control symptoms.
What research still needs to be done?
Unresolved questions include whether different forms of the hormones, lower doses, different hormones, or different methods of administration are safer or more effective; whether risks and/or benefits persist after women stop taking hormones; whether women might be able to take hormones safely for a short period of time; and whether certain subgroups of women might be at higher or lower risk than the general population.
The WHI continues to evaluate the effects of calcium and vitamin D supplements and of a diet low in fats and high in fruits, vegetables, and grains on the prevention of breast cancer, colorectal cancer, and heart disease (18).
Several studies to evaluate the safety and effectiveness of complementary and alternative therapies such as soy products are under way (19).
Where can people get more information about menopausal hormone use?
The following resources provide additional information about menopausal hormones and the WHI:
NIH Menopausal Hormone Therapy Home Page (http://www.nih.gov/PHTindex.htm).
WHI Participant Web site (http://www.whi.org).
NCI Menopausal Hormone Use digest page (http://www.cancer.gov/clinicaltrials/digest-postmenopausal-hormone-use).
NHLBI Postmenopausal Hormone Therapy Web site (http://www.nhlbi.nih.gov/health/women/).
National Center for Complementary and Alternative Medicine (NCCAM) Menopause Treatments Web page (http://nccam.nih.gov/health/menopause.htm).
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Works Cited: |
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Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association 2002; 288(3):321–333.
Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association 2004; 291(14):1701–1712.
Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women’s Health Initiative randomized trial. Journal of the American Medical Association 2003; 289(24):3243–3253.
Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. Journal of the American Medical Association 2006; 295(14):1647–1657.
Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362(9382):419–427.
Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. Journal of the National Cancer Institute 2000; 92(4):328–332.
Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. Journal of the American Medical Association 2000; 283(4):485–491.
Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: A meta-analysis. Obstetrics and Gynecology 1995; 85(2):304–313.
Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: The Women’s Health Initiative randomized trial. Journal of the American Medical Association 2003; 290(13):1739–1748
Beral V, Bull D, Reeves G, Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005; 365(9470):1543–1551.
Lacey JV Jr., Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. Journal of the American Medical Association 2002; 288(3): 334–341.
Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. Journal of the American Medical Association 2001; 285(11):1460–1465.
Riman T, Dickman PW, Nilsson S, et al. Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. Journal of the National Cancer Institute 2002; 94(7):497–504.
Seifert M, Galid A, Kubista E. Estrogen replacement therapy in women with a history of breast cancer. Maturitas 1999; 32(2):63–68.
Burger CW, van Leeuwen FE, Scheele F, Kenemans P. Hormone replacement therapy in women treated for gynaecological malignancy. Maturitas 1999; 32(2):69–76.
O’Meara ES, Rossing MA, Daling JR, et al. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. Journal of the National Cancer Institute 2001; 93(10):754–762.
Schairer C, Gail M, Byrne C, et al. Estrogen replacement therapy and breast cancer survival in a large screening study. Journal of the National Cancer Institute 1999; 91(3):264–270.
The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Controlled Clinical Trials 1998; 19(1):61–109.
Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: A randomized controlled trial. Journal of the American Medical Association 2004; 292(1):65–74.
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