Box 3

Hormone Therapy Schedules

• Cyclic or sequential–Estrogen for 25 or 30 days a month, with progestin added for 10-14 days
• Continuous-combined–Estrogen and progestin daily

Box 4

Alternatives to Hormone Therapy to Help Prevent Postmenopausal Conditions and Relieve Menopausal Symptoms

You may want to consider alternatives to hormone therapy to ease menopausal symptoms. The list below includes some locally applied hormone products (which may not carry the same risks as those that deliver medication throughout the body), dietary supplements, and lifestyle measures. Talk with your doctor or other health care provider about the best treatment for you for each symptom.

Be aware that, unlike drugs, the U.S. Food and Drug Administration (FDA) does not have the authority to approve dietary supplements before they are sold. The dietary supplement manufacturer is responsible for insuring that the product is safe and that any representations or claims made about it are adequately substantiated and not false or misleading (see Box 5).

One positive move you can make to feel better is to adopt a healthy lifestyle–don't smoke, eat a variety of foods low in saturated fat and cholesterol and moderate in total fat, maintain a healthy weight, and be physically active.

For postmenopausal conditions:

Osteoporosis

• See Box 20 for lifestyle behaviors to protect bone density
• Designer estrogen Raloxifene (Evista), which preserves bone density
• Bisphosphonates Actonel or Fosamax, which reverse bone loss and prevent fractures
• Calcitonin (a nasal spray), which may prevent fractures
• Note: Phytoestrogens (see "Hot flashes" below) have not been shown to reduce fractures

Heart disease

• Lifestyle behaviors, including:
  • Following a healthy eating plan
  • Limiting consumption of alcoholic beverages
  • Not smoking
  • Maintaining a healthy weight
  • Being physically active
• Preventing and controlling high blood pressure
• Preventing and controlling high blood cholesterol
• Managing diabetes
• Taking prescribed medication to control heart disease

For menopausal symptoms:

Hot flashes

• Lifestyle changes. These include dressing and eating to avoid being too warm, sleeping in a cool room, and reducing stress. Avoid spicy foods and caffeine. Try deep breathing and stress reduction techniques, including meditation and other relaxation methods.
• Soy. This contains phytoestrogens. (Phytoestrogens are estrogen-like substances derived from a plant source.) However, there is no solid evidence that soy–or other sources of phytoestrogens–really do relieve hot flashes. Further, the risks of taking soy, especially the more concentrated forms of soy, such as pills and powders, are not known. Phytoestrogens from soy can be consumed through foods or supplements. Soy food products include tofu, tempeh, soy milk, and soy nuts. These soy products are more likely to work on mild hot flashes.
• Other sources of phytoestrogens. These include such herbs as black cohosh, a member of the buttercup family, wild yam, dong quai, and valerian root.
• Antidepressants, such as Effexor, Paxil, and Prozac. These have been proved moderately effective in clinical trials.

Vaginal dryness

• Vaginal lubricants and moisturizers (available over the counter).
• Products that release estrogen locally (such as vaginal creams, a vaginal suppository, called Vagifem, and a plastic ring, called an Estring)–these are used for more severe dryness. The ring contains a low dose of estrogen and may not protect against osteoporosis. It also must be changed every 3 months.

Mood swings

• Lifestyle behaviors, including getting enough sleep and being physically active
• Relaxation exercises
• Antidepressant or anti-anxiety drugs

Insomnia

• Over-the-counter sleep aids
• Milk products, such as a glass of milk or cup of yogurt–choose low- or fat-free varieties
• Do physical activity in the morning or early afternoon– exercising later in the day may increase wakefulness
• Hot shower or bath immediately before going to bed

Memory problems

• Mental exercises
• Lifestyle behaviors, especially getting enough sleep and being physically active

Box 5

About Dietary Supplements

If you use dietary supplements to try to ease hot flashes and other menopausal symptoms, you should bear these points in mind: The U.S. Food and Drug Administration (FDA) does not have the authority to approve dietary supplements before they are marketed, and it's important to tell your health care provider that you are taking such remedies.

Dietary supplements are sold over the counter and may contain phytoestrogens: These are estrogen-like substances that come from some plants (such as soy) and plant materials (such as legumes, vegetables, cereals, and some herbs). For instance, these products may contain black cohosh, wild yams, dong quai, and valerian root.

Dietary supplement manufacturers are responsible for making sure that their products are safe. The FDA must show that a dietary supplement is harmful before it can limit the product's use or remove it from the market. Currently, there are no FDA regulations that specifically establish minimum standards for the manufacture of dietary supplements in order to insure their identity (tests to insure that the ingredient is actually what its label claims), purity, quality, strength, and composition. You may want to contact a product's manufacturer before buying it.

Furthermore, the possible effects of the products are not known. Some of the substances they contain are being studied. For example, soy contains plant estrogens, which are being studied to see if they have the same risks and benefits as estrogen.

Some of this research is being supported by the Office of Dietary Supplements, the National Center for Complementary and Alternative Medicine, the National Institute on Aging, and other units of the National Institutes of Health.

Until more is known about these substances, you should use them with caution. Also, as noted, tell your health care provider if you take a dietary supplement or if you increase your intake of dietary phytoestrogens. There may be dangerous side effects. An increase in the level of estrogens in your body could interfere with other prescription medications you are taking or even cause an overdose.

Box 6

What We Lean From Different Types of Studies

Medical researchers conduct many types of studies. The reason is that the studies yield different kinds of information. Together, the studies help scientists understand health and disease, and how to educate people so they can lead healthier lives.

Three main types are: observational studies, clinical trials, and community prevention studies. Each type is discussed briefly below:

Observational studies follow women's medical and lifestyle practices but do not intervene. Such studies can turn up possible relationships between various factors and health or illness. Those factors include population traits, ethnicity, genetic attributes, and behaviors. For instance, researchers can track women who do and do not take postmenopausal hormone therapy. The results may show that the hormone users have fewer heart attacks. But the results cannot conclude that hormone therapy reduces the risk of heart disease. Other factors may have played a part. For instance, compared with women who do not use hormone therapy, those who do are often healthier, have a higher level of education and better access to medical care, and are more willing to follow a prescribed therapy.

Clinical trials control and compare specific medical interventions, such as the use of postmenopausal hormone therapy. Women on an intervention are compared with those who do not receive the treatment. Researchers try to control all of the experimental conditions so that any difference between the two groups can be tied to the intervention.

The most rigorous of these investigations is the randomized, controlled, double-blinded clinical trial. Women are randomly assigned to the study groups and, in a drug trial for instance, neither the women nor the researchers typically know who is receiving an active drug and who a placebo. Further, on average women in the two groups will be similar in age, education, health at the time of entering the trial, and other factors that may affect the results. These trials are considered to be the "gold standard" among types of studies because they yield the most reliable information. Clinical trials are often done to test whether a possible relationship uncovered in an observational study is in fact so. The trials help establish a causal link between a treatment and a specific medical outcome, such as fewer heart attacks.

Community prevention studies explore ways to encourage people to adopt healthier behaviors.

Box 7

Risk Factors for Uterine Cancer

There are various types of uterine cancer. The most common is endometrial cancer, which begins in the lining (endometrium) of the uterus. It is often referred to as uterine cancer.

Key risk factors for uterine cancer are:

• Age–usually occurs after age 50
• Endometrial hyperplasia–an increase in cells in the lining of the uterus
• Hormone therapy–using estrogen without progesterone
• Obesity and related conditions
• Tamoxifen–taken to prevent breast cancer
• Race–white women are more likely than African American women to develop uterine cancer
• Colorectal cancer–those who have an inherited form are at a higher risk of developing uterine cancer
• Factors that increase exposure to estrogen–not having children, starting menstruation at an early age, entering menopause late

Box 8

Breast Cancer Risk Factors

About 80 percent of breast cancer cases occur after age 50. One of every eight American women who live to be 85 develops breast cancer. Some factors increase the risk for breast cancer. However, most women who develop breast cancer do not have any of the risk factors.

Key factors that increase the risk of developing breast cancer are:

• Personal history–if you've had it once, you're more likely to develop it again
• Family history–if your mother, sister, or daughter had breast cancer, especially at an early age, you're more likely to develop it
• Other breast changes (not including ordinary "lumpiness")–such as atypical hyperplasia (an irregular pattern of cell growth)
• Genetic alterations–changes in certain genes, including BRCA1 and BRCA2 mutations

Other factors also may increase the risk of developing breast cancer. These include:

• Race–white women are more likely to develop it than African American or Asian women
• Estrogen exposure–risk is somewhat increased for those who began menstruation early (before age 12), had menopause late (after age 55), never had children, or took hormone therapy for long periods
• Late childbearing–having a first child after about age 30
• Radiation therapy–if given to the chest more than 10 years ago, especially in women younger than age 30
• Breast density–breasts with a high proportion of lobular and ductal tissue, which is dense and in which breast cancers usually appear
• Alcoholic beverage consumption

Box 10 [skip to text version]

Estrogen Plus Progestin Pills vs. Placebo Pills

The rate of the following medical conditions per 10,000 women per year

Box 10 Text Version [skip to graphical version]

Estrogen Plus Progestin Pills vs. Placebo Pills

The rate of the following medical conditions per 10,000 women per year

Box 11

What Do the Data Really Mean?

The data sound scary–and confusing. A 41 percent increase in strokes. A 34 percent decline in hip fractures. Which is more important? The bad news, or the good?

Either way, the percentages sound big. So it's good to take a moment and check out what they're really saying.

There are two main ways to express risk–"relative risk" and "absolute risk." The relative risk measures and compares the percent change in risk of some health-related event in a population that has been exposed to some agent and another that has not. The increase (or decrease) in absolute risk is an estimate of the number or proportion of women who will (or will not) develop a disease when exposed to a particular agent.

Relative risk allows scientists to compare data. In the WHI study, for example, scientists wanted to find out the relative risk of breast cancer in women who had and had not been exposed to the estrogen plus progestin hormone therapy. After about 5 years, the study had 166 cases of breast cancer among estrogen plus progestin users, compared with 124 in the placebo group. However, there were more woman in the hormone group–8,506, compared with 8,102 in the placebo group. To be able to compare data from the groups, the cases were converted into rates per 10,000 women per year. Thus, the rate of breast cancer in the hormone group was 38 per 10,000 women, compared with 30 per 10,000 women in the placebo group. This also can be expressed as 38 divided by 30 or 1.26. Since that is 0.26 greater than an equal risk (or 1.00), the women on hormone therapy had a 26 percent greater chance of developing breast cancer than non-users.

What was the increase in absolute risk of developing breast cancer for women in the WHI study? On average, in any single year, 0.08 percent more women in the hormone group developed breast cancer than women in the placebo group. This means that, if a group of 10,000 women takes estrogen plus progestin for a year, there will be 8 more cases of breast cancer among the hormone users than if they hadn't taken the therapy. Thus, women on the hormone therapy have only a slightly increased absolute risk of breast cancer over a year. (See Boxes 9 and 10 for a summary of the relative and absolute risks of breast cancer and other conditions for women in the estrogen plus progestin study.)

But, if you count up all the added cases of breast cancer, heart attacks, strokes, and blood clots in the lungs and subtract the fewer cases of colorectal cancer and hip fractures, you'd still get about 100 extra harmful events among the 10,000 hormone users after 5.2 years–the period the study ran. Multiply that by 10 years and millions of women and the number of cases of adverse effects grows.

Remember too that reports of increased risks do not mean you will develop breast cancer or another condition if you have been using the hormone therapy. Your personal and family medical history, along with your lifestyle and other influences, play a big role in your chance of developing a disease.

Box 12

Risk Factors for Stroke

Main risk factors are:

• High blood pressure
• Diabetes
• Cigarette smoking

Other risk factors include:

• Family history–stroke appears to run in some families, whether due to genetics and/or shared lifestyle
• Heavy consumption of alcoholic beverages
• High blood cholesterol
• Menopause

Box 13

Risk Factors for Colorectal Cancer

About 30,000 women a year die of colorectal cancer–it is the third-leading cause of cancer deaths for women, after lung and breast cancers.

Factors that increase the risk of colorectal cancer include:

• Age–risk increases after age 50
• Diet–eating a diet high in fat and calories, and low in fiber
• Polyps–these are benign growths on the inner wall of the colon and rectum
• Personal medical history–having had cancer of the ovary, uterus, or breast; also having had colorectal cancer once increases the chance of developing it again
• Family medical history–having first-degree relatives (parents, siblings, or children) with colorectal cancer, especially at a young age; risk increases even more if many family members have had colorectal cancer
• Ulcerative colitis–a condition in which the lining of the colon becomes inflamed

Box 14

Postmenopausal Hormone Therapy and Ovarian Cancer Risk

Early studies of postmenopausal hormone therapy found inconsistent results about its effect on the risk of ovarian cancer: Some reported increased risk with estrogen use, while others reported no effect or even a protective one. Most of those studies were relatively small and did not take into account the key risk factors for ovarian cancer (see Box 15).

More recently, two large observational studies have indicated that long-term estrogen use increases the risk of ovarian cancer. It's important to keep in mind that observational studies do not prove that a treatment causes a disease (see Box 6). The evidence from these studies is cautionary, not definitive.

Here's more on the studies:

• One study followed 211,581 postmenopausal women from 1982-1996. Of those, 44,260 had used estrogen-only hormone therapy; the rest did not use hormone therapy. None of the women had had a hysterectomy, ovarian surgery, or cancer. Those with 10 or more years of estrogen use had an increased risk of dying from ovarian cancer–and, while the risk decreased somewhat long after use was stopped, it was still higher than that of women who had never used estrogen-only therapy.
• Another study followed 44,241 women from 1979-1998. It found that estrogen-only therapy increased the risk of ovarian cancer. Women who used estrogen alone for 10 or more years had an 80 percent higher risk of ovarian cancer than women who had never used the hormone therapy; women who used estrogen alone for 20 or more years had a 220 percent higher risk than women who had never used hormone therapy.
  
  The study found no increased risk of ovarian cancer for users of estrogen plus progestin. However, few women in the study had used the combination therapy for more than 4 years.

More research is needed to see if estrogen plus progestin affects ovarian cancer risk–and on other aspects of postmenopausal hormone use. For instance, another recent study found that estrogen alone or estrogen plus progestin used on a sequential basis increased the risk for ovarian cancer, while estrogen plus progestin used continuously did not.

Box 15

Risk Factors for Ovarian Cancer

About 1 in 57 American women will develop ovarian cancer. Most will be over age 50, but younger women also can develop the disease.

Here are some factors that increase or decrease the risk of ovarian cancer:

Increases risk

• Age–risk increases as a woman ages
• Family history of ovarian cancer–higher risk if mother or sister has had ovarian cancer; somewhat higher risk if other relatives, such as grandmother, aunt, or cousin, have developed ovarian cancer
• Postmenopausal hormone therapy–may increase risk
• Fertility drugs
• Personal history of breast and/or colon cancer

Decreases risk

• Oral contraceptives–the longer the use, the lower the risk may be and the decrease may last after use has ended
• Childbearing and breast-feeding
• Tubal ligation (sterilization) or hysterectomy
• Prophylactic (to prevent or protect) oophorectomy (surgery to remove one or both ovaries)

Box 16

What About Birth Control Pills?

The recent findings about the risks of long-term postmenopausal hormone therapy do not apply to use of birth control pills, which have not been found to increase breast cancer risk.

There had been concern about the effect of birth control pills on the risk of breast cancer because, until recently, studies had given conflicting results. For example, a 1996 analysis of 54 small studies had found a slight increase among women who were or had recently used oral contraceptives. But the 54 studies differed in quality and some included oral contraceptive preparations no longer in use. Other studies, such as the 1986 "Cancer and Steroid Hormone" (CASH) study, had found no increased risk.

In June 2002, findings of the "Women's Contraceptive and Reproductive Experiences Study" (also called the Women's CARE Study) were released and showed no increased risk of breast cancer, regardless of length of oral contraceptive use, timing of use, age at use, or the users' risk factors for developing breast cancer. The study, supported by the NIH's National Institute of Child Health and Human Development, involved more than 9,257 women between the ages of 35 and 64. The women were interviewed about their contraceptive use.

Oral contraceptives do pose risks, however: Combination oral contraceptives increase the risk of blood clots. Oral contraceptives should not be used if you are at an elevated risk for blood clots because of diabetes or another condition, or if you smoke. Taking oral contraceptives and smoking increases your risk for heart attack and stroke.

Oral contraceptive use has benefits too: It can reduce the risk of ovarian cancer, endometrial cancer, colorectal cancer, pelvic inflammatory disease (an infection that can lead to infertility), and osteoporosis.

Box 17

Talking With Your Doctor

It's important to be involved in your health care. Ask questions and express your concerns. Here are some questions that may help you talk with your health care provider about hormone therapy:

• Why am I taking hormone therapy? Or why should I take hormone therapy?
• Which hormone therapy am I on?
• What are my risks for heart disease, breast cancer, and osteoporosis?
• Should I stop taking the hormone therapy?
• What's the best way for me to stop? What side effects will I have?
• Is there an alternative therapy that I can use long-term?
• What alternatives can help me prevent heart disease?
• What alternatives can help me prevent osteoporosis?
• What can I do to keep menopausal symptoms from returning?

Your risk for heart disease, osteoporosis, and colorectal cancer may change over time. So remember to regularly review your health status with your doctor or other health care provider.

It's also important to bear in mind that your doctor or other health care provider may not be able to answer all of your questions–many questions about postmenopausal hormone use remain. For instance, it's not yet known if increases in disease risk caused by long-term use of estrogen plus progestin drop after use stops. As with any treatment, you need to carefully weigh your personal risks against the possible benefits and make the best choice possible for your health and lifestyle needs.

Finally, your doctor or other health care provider can speak with a WHI Principal Investigator about the study's results. For a list of the Principal Investigators, check the NHLBI WHI Web site or contact the NHLBI Health Information Center.

Box 18