For decades, women have used hormone replacement therapy (HRT, also known as postmenopausal hormone therapy) because of its ability to relieve menopausal symptoms such as hot flashes. Many doctors and their patients believed HRT had other positive health benefits as well. However, recent studies have called some of these beliefs into question.

The purpose of this document is to discuss what is known about how hormone replacement therapy (HRT) can affect a woman's risk of getting certain cancers. It does not discuss in detail the possible effects of HRT on other diseases such as osteoporosis (bone thinning), heart disease, and dementia.

This is not meant to be a policy statement of the American Cancer Society -- it is a summary of medical articles on the subject. Women are encouraged to discuss this information with their doctor. A woman and her doctor may decide that hormones are or are not needed for a period of time for her menopausal symptoms.

Background

Menopause is the period in a woman's life when her ovaries stop releasing egg cells and begin to make smaller amounts of the 2 main female hormones, estrogen and progesterone. Eventually, this results in the end of menstrual periods. Women who have their ovaries removed by surgery (oophorectomy) or whose ovaries stop functioning for other reasons also go through menopause, although not as gradually.

Lowered hormone levels cause the symptoms that are often associated with menopause -- hot flashes, dryness and thinning of vaginal tissues, and mood swings. Low estrogen levels also increase a woman's risk of other health problems, such as osteoporosis.

Estrogen replacement therapy

Estrogen replacement therapy (ERT) is used to raise estrogen levels in the body. CEE (conjugated equine estrogens) forms of ERT (such as Premarin^®) are most common and have been used for the longest time.

Combined hormone replacement therapy

Combined hormone replacement therapy (HRT) uses both estrogen and progestin (progesterone-like hormone). Combined HRT can be given 2 ways:

• Continuous HRT involves giving the same dose of estrogen and progestin each day. 
• Sequential (cyclical) HRT uses differing amounts of the hormones during a month-long period to mimic natural menstrual cycles.

ERT and combined HRT are sometimes used to relieve menopausal symptoms. Some doctors believe hormone therapy can also lower a woman's risk of some other health problems linked to low estrogen levels.

How Hormone Therapy Is Given

Both ERT and combined HRT may be given as a systemic therapy. This means that the hormones are given as pills or as a patch. They are absorbed through the digestive system or the skin and reach all parts of the body through the bloodstream. As another option, hormone treatments may be applied topically. This means they only reach certain areas rather than the whole body. With topical use, smaller amounts of hormones are placed inside the vagina in cream, ring, or tablet forms that slowly release hormones to nearby tissues.

Endometrial (Uterine) Cancer

ERT

The use of systemic estrogen (ERT) by itself increases a woman's risk of developing endometrial cancer (cancer of the lining of the uterus). Use of vaginal tablets, creams, or rings containing estrogen over a long time may also increase estrogen levels in the body. The risk continues to be increased even after ERT is no longer used.

For these reasons, estrogen alone is almost never given to women who have gone through menopause and who still have a uterus.

Combined HRT

For women who still have their uterus, studies show that combined HRT (progestin and estrogen) may provide the benefits of estrogen replacement without increasing the risk of endometrial cancer.

One study showed that about 1 in 9 women treated with estrogen alone for 3 years developed a type of pre-cancerous change in their endometrium called atypical hyperplasia. Women treated with both types of hormones did not develop this change any more often than women not taking any hormones.

The Women's Health Initiative (WHI), a large, randomized, controlled trial of women getting either continuous combined HRT or a placebo (an inactive substance used for comparison, also known as a sugar pill) also found that combined HRT did not increase endometrial cancer risk. However, more of the women getting HRT had abnormal vaginal bleeding (a possible sign of endometrial cancer) that needed further testing.

A woman who has had her uterus completely removed (total hysterectomy) is not in danger of developing endometrial cancer, regardless of whether she takes ERT or HRT. But because the only reason for giving progestin is to protect the endometrium, a woman without a uterus would generally be given ERT alone.

Breast Cancer

Combined HRT

Results from the Women's Health Initiative (WHI) and many other studies have shown that daily use of combined HRT increases a woman’s chance of developing breast cancer by about 5% to 6% with each year of use .For example, if you took HRT for three years, your risk of breast cancer would be 15% to 18% higher than it was before you took HRT. This means the longer HRT was used the more the risk increased. Women who took this combined HRT also had a higher risk of having breast cancer detected at a more advanced stage and were more likely to have abnormal results on mammograms.

Not all of the questions surrounding combined HRT and breast cancer risk have been answered. Most of the increased risk of breast cancer from combined HRT is thought to be due to the progestin. Doctors are now looking at whether the dose of progestin can be decreased to lower the risk of breast cancer while still protecting the endometrium.

Women who no longer have a uterus (due to hysterectomy) should receive ERT instead of combined HRT. These women do not need progestin to protect against uterine cancer and are increasing their risk of breast cancer by taking combined HRT.

The risk of HRT applies only to current and recent users. A woman's breast cancer risk decreases after stopping HRT and appears to return to that of the general population (the usual risk) within 5 years of stopping.

ERT

A separate part of the WHI looked at women who had had a hysterectomy, and whose ovaries were either removed or had stopped functioning. Those who were taking only estrogens did not have an increased risk of breast cancer.

The British "Million Women Study," and many other similar studies, reported a very slight increase risk of breast cancer (about 1% to 3% per each year of use) among women who took ERT.

Ovarian Cancer

Ovarian cancer is relatively rare, so it is hard to study whether something increases a woman's risk for it. Even when the relative risk (or probability) is found to be increased, a woman's absolute risk is still likely to be low. For example, a woman is much more likely to be affected by a 50% increase in her risk for breast cancer than by a 50% increase in her risk for ovarian cancer, because her risk for ovarian cancer is much lower to begin with. To put this another way, in a group of 100 women with a 12% risk of breast cancer and a 2% risk of ovarian cancer, you would expect about 2 cases of ovarian cancer and 12 breast cancers. A 50% risk increase in both cancers would mean there would be 18 women with breast cancer but only 3 with ovarian. So each woman's absolute risk of ovarian cancer would still be much lower than her risk of breast cancer.

ERT

Several studies have shown that women who take ERT have higher risk for ovarian cancer compared to women who take no hormones after menopause. The risk of ovarian cancer increases the longer a woman uses ERT, particularly among those who have used ERT for more than 10 years.

Combined HRT

Whether HRT increases risk of ovarian cancer is still uncertain. In one recent study, women who took estrogen and progesterone therapy (either continuously or sequentially) did not have a higher risk for ovarian cancer unless they previously took estrogen alone for a period of time without any progesterone.

The Women's Health Initiative study found that continuous combined HRT may increase the risk of ovarian cancer slightly, but this finding may have been due to chance because of the small number of women who developed ovarian cancer during the study.

Colon Cancer

Combined HRT

The Women's Health Initiative (WHI) study found that combined HRT reduced the risk of colorectal cancer by about 40%. This reduction has also been found in similar studies. Of course, these results must be weighed along with the effects of HRT on the risk of other types of cancer, as well as its effects on non-cancerous conditions.

ERT

In the estrogen-only arm of the WHI, estrogen replacement therapy did not seem to have any effect on the risk of colorectal cancer.

Conclusions

The decision to use hormone replacement therapy (ERT or HRT) after menopause should be made by each woman and her doctor after weighing the possible risks and benefits. Factors to consider include:

• the risk of breast, endometrial, and ovarian cancer; 
• the risks of other serious conditions affected by ERT or HRT not discussed here, such as heart disease, stroke, and serious blood clots (DVT or deep vein thrombosis); 
• the availability of other medicines that may treat menopausal symptoms or osteoporosis. 
• Other factors to consider would include how severe the woman's menopausal symptoms are and the type and dose of the hormones the doctor recommends.

If a woman and her doctor decide that ERT or HRT is appropriate to treat specific menopausal symptoms or health problems, it is often used at the lowest dose that works in her case and for as short a time as possible. Other treatments for these symptoms and conditions should also be considered.

It is important that any woman taking ERT or HRT be checked yearly by her doctor for any signs of cancer.

All women should report any vaginal bleeding that happens after menopause to their doctor without delay – it may be a sign of endometrial cancer.

Women should follow American Cancer Society guidelines for cancer early detection, especially those for breast cancer. These guidelines are in Breast Cancer: Early Detection. You can also order print copies by calling 1-800-ACS-2345.

The addition of progestin to estrogen (combined HRT) reduces the risk of endometrial cancer, but may not eliminate it entirely. If you are using vaginal cream, rings, or tablets containing estrogen talk to your doctor about follow-up and the possible need for progestin treatment.

For women who have had a total hysterectomy (removal of the uterus), the addition of progestin is not necessary because there is no risk of endometrial cancer. Adding progestin does not protect against breast cancer and, in fact, raises the risk further, so ERT is a better option.

In recent years, several over-the-counter "natural" products have been marketed to help with menopausal symptoms, including certain vitamins, soy-based products, and herbal products (such as black cohosh and red clover). These products are considered dietary supplements (as opposed to drugs) and have not been evaluated by the Food and Drug Administration for their safety or effectiveness. Studies are now being done to help determine if these products are effective or if they are any safer than the hormone replacement therapy drugs now in use.

Additional Resources

National Organizations and Web Sites*

Food and Drug Administration (FDA)
Telephone: 1-888-463-6332
Internet Addresses
Home Page: www.fda.gov
Menopause & Hormones Page:
www.fda.gov/womens/menopause/

National Cancer Institute
Telephone: 1-800-4-CANCER (1-800-422-6237)
Internet Addresses
Home Page: www.cancer.gov
Menopausal Hormone Use Page:
www.cancer.gov/clinicaltrials/digest-postmenopausal-hormone-use

National Institutes of Health
Telephone: 1-301-496-4000
Internet Addresses
Home Page: www.nih.gov
Menopausal Hormone Therapy Information Page:
www.nih.gov/PHTindex.htm

National Women's Health Information Center
Telephone: 1-800-994-WOMAN (1-800-994-9662)
Internet Addresses
Home Page: www.4women.gov
Menopause & Hormone Therapy Page:
www.4women.gov/Menopause/

*Inclusion on this list does not imply endorsement by the American Cancer Society.


References

Anderson GL, Judd HL, Kaunitz AM, Barad DH, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: The Women’s Health Initiative randomized trial. JAMA.2003; 290(13):1739-1748.

Beral V, Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003; 362(9382):419-427.

Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA. 2003; 289:3243-3253.

Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Eng J Med. 2004; 350(10):991-1004.

Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst. 1998; 90(11):814-823.

Fletcher SW, Colditz, GA. Failure of estrogen plus progestin therapy for prevention. JAMA.2002; 288(3):366-367.

Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk of breast cancer with a favorable histology: Results of the Iowa Women's Health Study. JAMA.1999; 281(22):2091-2097.

Lacey JV, Mink PJ, Lubin JH, Sherman ME, et al. Menopausal hormone replacement therapy and ovarian cancer. JAMA. 2002; 288(3):334-341.

Li CI, Malone KE, Porter PL, Weiss NS, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA. 2003; 289:3254-3263.

National Cancer Institute. Menopausal Hormone Use: Questions and Answers. Available online at: www.cancer.gov/newscenter/estrogenplus. Accessed September 2004.

Newcomb PA, Longnecker MP, Storer BE, Mittendorf R, et al. Long-term hormone replacement therapy and risk of breast cancer in postmenopausal women. Am J Epidemiol. 1996; 143(5):527.

Noller, KL. Estrogen replacement therapy and risk of ovarian cancer. JAMA. 2002; 288(3):368-369.

Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000; 283(4):485-491.

Weiderpass E, Adami HO, Baron JA, Magnusson C, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst. 1999; 91(13):1131-1137.

Weiderpass E, Baron JA, Adami HO, Magnusson C, et al. Low-potency estrogen and risk of endometrial cancer: a case-control study. Lancet. 1999; 353(9167):1824-1828.

Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA. 2004; 291(14):1701-1712.

Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288(3):321-333.

Revised: 09/07/2007