Menopausal Hormone Replacement Therapy and Cancer Risk

For decades, women have used hormone replacement therapy (HRT) to ease symptoms of menopause, such as hot flashes. HRT is also known as post-menopausal hormone therapy, and you may see it abbreviated as PHT, MHT (for menopausal HT), or just HT. Many doctors and their patients believed HRT had other health benefits besides helping menopause symptoms. But studies have led doctors to question some of these beliefs.

Here we will discuss what is known about how HRT can affect a woman's risk of getting certain cancers. We will not go into the possible effects of HRT on other diseases like 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 published medical studies on the subject. Women who are thinking about using HRT should talk with their doctors about the information covered here. Women should also understand the risks and benefits of HRT and the follow-up they will need if HRT is used. Based on this information, a woman and her doctor may decide that hormones are or are not needed for a period of time to help with symptoms of menopause.

Menopause, symptoms, and hormone replacement therapy

Menopause is the time in a woman's life when her ovaries stop releasing eggs and start making smaller amounts of the 2 main female hormones, estrogen and progesterone. Over time, this causes menstrual periods to stop. Women who have their ovaries removed by surgery (oophorectomy) or whose ovaries stop working for other reasons go through menopause, too, but much more suddenly.

Lowered hormone levels cause the symptoms that are often linked to menopause -- hot flashes and night sweats, for instance. These symptoms tend to fade away at some point, whether or not they are treated. Other symptoms, like dryness and thinning of vaginal tissues can start later and may get worse over time. Low estrogen levels also increase a woman's risk of other health problems like osteoporosis.

Types of hormone replacement therapy

Several terms are used to describe the hormones given to a woman whose hormone levels are low due to menopause. You may hear any of these terms (HRT, PHT, MHT, and HT), but here we will use the term hormone replacement therapy or HRT.

HRT can mean estrogen and progestin used together, but can also refer to estrogen alone. It is important to know which type of HRT you are talking about when looking at the risks. In this discussion, we will use estrogen replacement therapy (ERT) to mean estrogen alone, and combined HRT to mean estrogen and progestin. Both types of HRT are discussed in detail below, along with the possible risks of each.

The word "bioidentical" is sometimes used by sellers to describe hormones that contain estrogens or progestins with the same chemical structure as those found naturally in people. "Bioidentical" or "natural" hormones that contain estrogens or progestins must be prescribed, just as other hormone drugs are, and should be assumed to have the same health risks as they do. For information on herbal remedies (that you can buy without a prescription), see "Herbs and supplements" in the section "What does it all mean?"

Estrogen replacement therapy (ERT): Estrogen alone

Estrogen replacement therapy 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. Estrogen alone is prescribed mainly for women who have had hysterectomies (surgery to remove the uterus or womb).

Combined hormone replacement therapy: Estrogen plus progestin

Combined HRT uses both estrogen and progestin (progesterone-like hormone). It is prescribed for women who have not had hysterectomies (they still have a uterus). Combined HRT can be given 2 ways:

• Continuous HRT means giving the same dose of estrogen and progestin each day.
• Sequential (cyclical) HRT uses different amounts of each hormone on specific days during the month so that the hormone levels are more like the natural menstrual cycle.

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

How hormone replacement therapy is given

Hormones that are given as pills or as a patch are absorbed through the digestive system or the skin and reach all parts of the body through the bloodstream. This type of therapy is referred to as a systemic treatment.

As another option, hormone treatments may be used topically. This means they mainly reach nearby areas rather than the whole body. Hormones that are placed in the vagina can enter the bloodstream, but the amount that gets in depends on the type of hormone and the dose. Dry or thinned vaginal tissues respond to very small doses of estrogen. These smaller doses are placed inside the vagina in the form of creams, rings, or tablets that slowly release hormones to the vagina and nearby tissues. Even though tiny amounts of hormone may enter the blood, most of it stays in the vaginal tissues. This is considered topical use.

Hormone replacement therapy and cancer risk

Several large studies have looked at the possible links between hormone replacement therapy and different types of cancer.

Hormone replacement therapy and endometrial (uterine) cancer risk

Estrogen replacement therapy (ERT) and uterine cancer risk

Using systemic ERT as a pill or patch increases a woman's risk of endometrial cancer (cancer of the lining of the uterus). The risk remains higher than average even after ERT is no longer used. Long-term use of vaginal creams, rings, or tablets containing estrogen may also increase the levels of estrogen in the body.

Because of this increased cancer risk, estrogen alone is almost never given to women who have gone through menopause and who still have a uterus.

Combined hormone replacement therapy (HRT) and uterine cancer risk

Studies show that combined HRT (progestin and estrogen) may help menopause symptoms in women who still have a uterus without increasing their risk of endometrial cancer.

One study showed that about 1 in 9 women treated with only estrogen 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 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. But 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 removed (hysterectomy) is not in danger of developing endometrial cancer, regardless of whether she takes ERT or combined HRT. But because the only reason for giving progestin is to protect the endometrium, a woman without a uterus is most likely to be given ERT alone.

Hormone replacement therapy and breast cancer risk

Combined hormone replacement therapy (HRT) and breast cancer risk

Results from the Women's Health Initiative (WHI) have shown that daily use of combined HRT increases a woman's chance of developing breast cancer by about 5% to 6% of the non-hormone risk with each year of use. To put this into numbers, if 10,000 women took combined HRT for a year, this would add up to about 8 more cases of breast cancer per year than if they had not taken HRT. The longer HRT was used, the more the risk increased.

In this study, women who took combined HRT also had a higher risk of having breast cancer detected at a more advanced stage and were more likely to have breast changes seen on mammograms.

But there are still questions about combined HRT and breast cancer risk. 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, but still protect the endometrium.

Women who have had hysterectomies should take 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.

HRT risks apply only to current and recent users. A woman's breast cancer risk is thought to decrease after she stops HRT and return to that of the general population (the usual risk) within 3 years of stopping.

Estrogen replacement therapy (ERT) and breast cancer risk

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

The British "Million Women Study," and many other studies like this, reported a very slight increase in breast cancer risk (about 1% to 3% increase per each year of use) among women who took ERT. This is lower than that found in the WHI study of estrogen plus progestin and breast cancer risk, as noted above.

Hormone replacement therapy and ovarian cancer risk

Ovarian cancer is rare, which makes it harder to study its risk factors. Even when something increases the relative risk (or probability) of developing ovarian cancer, 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% lifetime 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. Still, because there are no good screening tools for it, and ovarian cancer is often fatal, even a small risk linked to HRT may be worth considering.

Estrogen replacement therapy (ERT) and ovarian cancer risk

Studies have shown that women who take ERT have a higher risk for ovarian cancer compared with women who take no hormones after menopause. The risk of ovarian cancer increases the longer a woman uses ERT. The largest study so far found that women who had used ERT for 5 or more years had about a 50% increased risk of developing ovarian cancer. This link was confirmed in another large study finding. The risk of ovarian cancer appeared to increase further the longer ERT was used.

Combined hormone replacement therapy (HRT) and ovarian cancer risk

It's still not known for certain if HRT increases the risk of ovarian cancer. The WHI 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. Other studies also suggest that HRT may increase risk slightly, but less than ERT does.

Hormone replacement therapy and colorectal cancer risk

Combined hormone replacement therapy (HRT) and colorectal cancer risk

The WHI study found that combined HRT reduced the risk of colorectal cancer by about 40%. This effect seemed to fade when the women were checked a little more than 2 years after the HRT was stopped. This risk reduction has also been found in other 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.

Estrogen replacement therapy (ERT) and colorectal cancer risk

In the WHI group that took estrogen only, estrogen replacement therapy did not seem to have any effect on the risk of colorectal cancer. Other studies have found a slightly lower risk of colorectal cancer in women who have used ERT for many years.

Hormone replacement therapy and lung cancer risk

Combined hormone replacement therapy (HRT) and lung cancer risk

The WHI study found that after about 5 years of combined HRT use and another 3 years of follow-up off the drugs, women who took HRT had an increased risk of dying from lung cancer, especially non-small cell lung cancer. But the risk of developing lung cancer was not significantly higher in women taking HRT than in the women who took the placebo. Some other, less rigorous studies have also looked at a possible link between combined HRT and the risk of getting lung cancer, but the results have been mixed.

Smoking is by far the most important cause of lung cancer. It is not clear if using combined HRT might somehow increase the chance of lung tumors forming, or if it might cause small, existing tumors to grow faster. But because it appears to raise the risk of dying from lung cancer, women who are at increased risk for lung cancer, such as smokers and ex-smokers, should discuss these results with their doctors when deciding whether to start or continue taking combined HRT.

Estrogen replacement therapy (ERT) and lung cancer risk

Researchers looked at the WHI study to see if there was a link between ERT and the risk of developing or dying from lung cancer. Estrogen alone did not increase either risk in the WHI study.

What does it all mean?

The decision to use hormone replacement therapy, either estrogen replacement therapy (ERT) or combined hormone replacement therapy (HRT), after menopause should be made by each woman and her doctor after weighing the possible risks and benefits. Things to think about include:

• The risk of breast, endometrial, ovarian, and lung cancer
• The risks of other serious conditions affected by HRT that are not covered here, like heart disease, stroke, and serious blood clots (DVT or deep vein thrombosis)
• Other medicines that may be used to treat menopausal symptoms or osteoporosis

Other factors to consider include how bad 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 combined HRT is the best treatment for certain symptoms of menopause or health problems, it is usually best to use it at the lowest dose that works for her 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 combined 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 doctors right away -- it may be a sign of endometrial cancer.

Women should follow the American Cancer Society guidelines for cancer early detection, especially those for breast cancer. These guidelines are in our document, Breast Cancer: Early Detection. To get these guidelines, please call 1-800-227-2345 or visit our Web site at www.cancer.org.

Adding 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 hysterectomy (surgery to remove the uterus), progestin does not need to be added 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 this case.

Herbs and supplements

In recent years, many over-the-counter "natural" products have been marketed to help with menopausal symptoms. These include certain vitamins, soy-based products, and herbal products (like 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 (FDA) for their safety or effectiveness. Some of the products have been tested, mostly in small clinical trials, but many of the tests had problems with the way they were done that could affect their outcomes. Well-controlled scientific studies are needed to help find out if these products work and if they are any safer than the HRT drugs now in use. You can learn more by reading How to Know What Is Safe: Choosing and Using Dietary Supplements. This is available on our Web site at www.cancer.org, or call us at 1-800-227-2345 to have it sent to you.

Additional resources

National organizations and Web sites*

Food and Drug Administration (FDA)
Toll-free number: 1-888-463-6332
Web site: www.fda.gov

Information on menopause in English and Spanish can be found at: www.fda.gov/ForConsumers/ByAudience/ForWomen/WomensHealthTopics/ucm117978.htm

National Cancer Institute
Toll-free number: 1-800-422-6237 (1-800-4-CANCER)
Web site: www.cancer.gov

Menopausal Hormone Replacement Therapy page: www.cancer.gov/clinicaltrials/digest-postmenopausal-hormone-use

National Institutes of Health
Telephone number: 301-496-4000
Web site: www.nih.gov

Menopausal Hormone Therapy Information page: www.nih.gov/PHTindex.htm

National Women's Health Information Center
Toll-free number: 1-800-994-9662 (1-800-994-WOMAN)
Web site: www.womenshealth.gov

Menopause & Hormone Therapy page: www.womenshealth.gov/Menopause/

No matter who you are, we can help. Contact us anytime, day or night, for information and support. Call us at 1-800-227-2345 or visit www.cancer.org.

References

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. JAMA. 2003;290:1739-1748.

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

Beral V, Million Women Study Collaborators. Ovarian cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2007;369:1703-1710.

Calle EE, Feigelson HS, Hildebrand JS, et al. Postmenopausal hormone use and breast cancer associations differ by hormone regimen and histologic subtype. Cancer. 2009;115(5):936-945.

Chlebowski RT, Anderson GL, Manson JE, et al. Lung Cancer Among Postmenopausal Women Treated With Estrogen Alone in the Women's Health Initiative Randomized Trial. J Natl Cancer Inst. 2010;102(18):1413-21.

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

Chlebowski RT, Kuller LH, Prentice RL, et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360(6):573-587.

Chlebowski RT, Schwartz AG, Wakelee H, et al. Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet. 2009;374:1243-1251.

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

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

Danforth KN, Tworoger SS, Hecht JL, et al. A prospective study of postmenopausal hormone use and ovarian cancer risk. BJC. 2007;96:151-156.

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

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;281:2091-2097.

Geller, SE, Studee L. Botanical and dietary supplements for menopausal symptoms: What works, what does not. J Women's Health. 2005;14:634-649.

Gold, EB, Flatt SW, Pierce JP, et al. Dietary factors and vasomotor symptoms in breast cancer survivors: The WHEL study. Menopause. 2006;13:423-433.

Heiss G, Wallace R, Anderson GL, et al, WHI Investigators. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299:1036-1045.

Hildebrand JS, Gapstur SM, Feigelson HS, et al. Postmenopausal hormone use and incident ovarian cancer: associations differ by regimen. Internat. J Cancer. 2010, in press.

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

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

Low Dog T. Menopause: a review of botanical dietary supplements. Am J Med. 2005;118:98-108.

National Cancer Institute Fact Sheet. Menopausal Hormone Replacement Therapy Use and Cancer: Questions and Answers. Accessed at www.cancer.gov/cancertopics/factsheet/Risk/menopausal-hormones on September 27, 2010.

Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy. JAMA. 2002;288:872-881.

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

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

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

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

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

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;291:1701-1712.

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;288:321-333.