Questions and Answers About Hormone Replacement Therapy

National Cancer Institute
Thursday, 23 August 2001

1. What is hormone replacement therapy?

Hormone replacement therapy (HRT) is treatment with hormones, either estrogen alone or in combination with progestin (preparations that have effects similar to that of progesterone), to replenish the natural hormones that decrease at menopause. Estrogen replacement therapy (ERT) refers to the use of estrogen alone (called unopposed estrogen).

About 12 million women in the United States take estrogen alone and about 8.6 million women are on the combined hormone regimen, according to drug company estimates. Data from a national survey showed that 45 percent of U.S. women born between 1897 and 1950 used HRT for at least one month and 20 percent continued use for five or more years (1).

2. What is menopause?

Menopause is the transition between a woman's childbearing years and her non-childbearing years. It is the last stage of a biological process during which the ovaries gradually produce lower levels of sex hormones - estrogen, progesterone, and testosterone. By the time natural menopause is complete (usually between ages 45 and 55) hormone output decreases significantly. In postmenopausal women, estrogen levels are about one-tenth the level of premenopausal women and progesterone is nearly absent. The low levels of estrogen after menopause are produced by the adrenal glands and fat cells. HRT usage approximately doubles the estrogen level of a postmenopausal woman. Therefore, even with HRT, estrogen and progesterone levels of a postmenopausal woman do not reach the natural levels of a premenopausal woman.

3. Why is hormone replacement therapy used?

Doctors may recommend using estrogen alone or in combination with progestin to counter some of the possible effects of natural or surgical menopause (removal of ovaries) on a woman's health and quality of life. Symptoms of menopause may include hot flashes, sleeplessness, and vaginal dryness.

Hormones may also be prescribed to prevent some long-term effects such as osteoporosis and coronary heart disease (CHD).

4. Why is estrogen plus progesterone recommended vs. estrogen alone?

Studies have shown that prolonged exposure of the uterus to estrogen without progesterone increases a women's risk of endometrial cancer (cancer of the uterine lining). By adding progestin to the estrogen regimen, the risk of endometrial cancer can be reduced to nearly the same level as women not using HRT (2). However, some studies have shown increases in endometrial cancer risk with the combined regimens if progestins are used for less than 10 days per month (3,4).

Generally, standard hormone replacement therapy for women who have undergone hysterectomy (surgical removal of uterus) is estrogen alone, whereas women who have not undergone this procedure are given the estrogen-progestin combination.

5. What is known about the benefits of HRT on blood cholesterol and heart disease?

Estrogen lowers LDL-cholesterol and raises protective HDL-cholesterol, providing a possible biological mechanism to support the use of estrogen in the prevention of coronary heart disease (CHD). (High levels of LDL-cholesterol in the blood lead to cholesterol build-up in the arteries whereas high levels of HDL-cholesterol help remove cholesterol from the blood and prevent fatty build-up.)

One clinical trial completed in the 1990s, the Postmenopausal Estrogen/Progestins Intervention (PEPI) trial, looked at changes in HDL, LDL, fibrogen, blood pressure, and serum insulin resulting from estrogen or estrogen/progestin use. The results showed that HDL was increased significantly, LDL and fibrogen levels were decreased significantly, and blood pressure and serum insulin levels were nearly unaffected (5).

Over the last 25 years, several observational studies in which women reported whether they had or had not used HRT have suggested a reduction in risk of as much as 25 percent to 50 percent for coronary heart disease in postmenopausal women using HRT (6). Most of the participants in these studies were healthy women at low risk for CHD. (CHD is the most common cause of death in older women. In 1997, about 498,000 women died of cardiovascular disease whereas about 42,000 women died of breast cancer, according to the latest figures from the National Center for Health Statistics.)

The majority of studies on the effect of HRT on cardiovascular disease and mortality have been conducted using estrogens alone; only a few have investigated the effects of combined progestogen (pharmaceutical preparations that have effects similar to those of progesterone) and estrogen therapy. One of those, the Nurses' Health Study, which followed 59,337 women for 16 years, evaluated the effects of estrogen vs. the estrogen-progestin combination on CHD. This study found that women taking the estrogen-progestin combination had a greater reduction in risk of a major coronary event compared with women who used estrogen alone. Risk was lower in both groups of users, compared to non-users (7).

The study also considered the effects of HRT in women with a prior history of heart disease. In these women, HRT reduced the risk of a major coronary event after two years of use, with increasing benefits associated with longer duration of hormone therapy. During the first year of HRT use, however, risk of heart disease increased by 25 percent. The study found no difference between the effect of estrogen alone and that of the estrogen-progesterone combination (8). Similar results were obtained in a randomized clinical trial, the Heart and Estrogen/Progestin Replacement Study (HERS), which looked at the effects of combined therapy on the heart (9).

6. What is known about the benefits of HRT on bone health?

Postmenopausal osteoporosis is characterized by decreased bone mass, deterioration of bone tissue, and high bone fragility, making bone fractures of great concern. Estrogen deficiency is the most common risk factor for osteoporosis in women.

Estrogen, with and without progestin, has been seen to be a protective and effective treatment against osteoporosis. However, some studies have shown that the beneficial effects of short-term therapy are not permanent; short-term use (three to five years) of estrogen to relieve symptoms of menopause did very little to prevent fractures from osteoporosis in women when they reached age 75 to 80 years of age (10, 11).

It is unclear whether HRT started later in life can provide the same bone-preserving benefits as HRT begun during menopause. Two studies have found that increases in bone density among women starting HRT later in life were comparable those in women who started HRT earlier (12, 13). However, a study that analyzed data on nonvertebral bone fractures from 22 randomized HRT trials found a reduction in fractures only among women who began HRT before age 60 (14).

7. How does HRT affect breast cancer risk and survival?

Over the last 25 years, numerous studies have examined the possible relationship between HRT and breast cancer. Some of the studies showed an increased risk while others did not.

A recent re-analysis of over 90 percent of breast cancer studies throughout the world showed an increased risk in breast cancer for women who used HRT for five years or longer. (The risk was seen not only in current users, but also in women who stopped therapy some time in the previous four years. No risk was seen in women who had stopped the therapy for more than four years.) Most of the women included in the re-analysis were on estrogen alone (15).

Recent studies have shown the risk of breast cancer to be greater among women using combination estrogen/progestin, compared to estrogen alone (16, 17). Both groups of hormone users had a higher risk of breast cancer than non-users. The risk increased with longer duration of use, and returned to the risk of non-users five or more years after use was stopped (17).

However, previous use of HRT appears to have survival benefits for women diagnosed with breast cancer (18). One study of breast cancer patients showed that users of HRT had lower mortality rates than nonusers. Most of these patients stopped using HRT at the time of diagnosis. However, this protective effect diminished with time.

8. Is there a risk of ovarian cancer associated with HRT use?

The results of studies on ovarian cancer and hormone use are inconsistent. Some studies have found a slight increase in risk of ovarian cancer among women using estrogen therapy. Many more studies, however, have found no association between HRT use and ovarian cancer risk (2, 19). Because most studies have followed women using unopposed estrogen, there is currently not enough data to assess the potential effects of combined therapy on ovarian cancer (19).

9. What are the mortality benefits associated with HRT use?

Studies have shown a slightly lower total mortality rate among postmenopausal women using HRT. On average, the mortality among users of postmenopausal hormones has been lower than that of women who do not use hormones, but the survival benefit has been seen to diminish with longer duration of use (7). It is not clear whether this reduction in mortality is entirely due to the biologic effect from the use of hormones or whether the women who use hormones are healthier, or receive better medical attention.

10. Are there other reported benefits or risks associated with HRT use?

There have been some reports that the use of HRT may improve a woman's mood and psychological well-being, though evidence for the use of estrogen as a therapeutic agent for symptoms such as irritability and depression are inconclusive (20). In addition, several studies have shown that estrogen use in postmenopausal women may delay the onset and decrease the risk of Alzheimer's disease (21, 22, 23, 24, 25).

Women with certain pre-existing heart conditions are usually advised not to take HRT. These conditions include a history of blood clots (venous thromboembolisms) and recent heart attacks. Several studies have shown the risk of blood clots among women currently using HRT to be two to three times higher than among non-HRT users (21). Increased cases of lung clots (pulmonary embolisms) and inflammation of veins (thrombophlebitis) have also been reported with HRT use (26).

Another reported risk associated with HRT use is the development of gallstones (27).

11. What are the risks of HRT use for women who have a previous cancer history?

Only a small amount of research has been done to look at the risks associated with HRT for women who have a history of endometrial cancer. A few small studies have found no evidence that HRT adversely influences survival and/or recurrence of the disease in these women (28). However, there have been no large, long-term studies to compare the potential benefits (protection against bone loss and heart disease) to the potential cancer risks. An ongoing study (ERT Study) sponsored by the National Cancer Institute, is designed to resolve the debate over whether women who have had early stage cancer of the uterus, or endometrial cancer, can safely take estrogen replacement therapy.

Even though the safety of replacing women's estrogens after breast cancer is uncertain (29), one study of breast cancer patients has reported that women who continued HRT following their diagnosis had a reduction in recurrence and mortality compared to women who had never used HRT (30). At least one trial is under way to further address this issue, but the results will not be available for several years (31, 32).

12. Does the route of administration of hormones make a difference?

Most of the data on the long-term health effects of hormones come from studies involving estrogen and/or progestin pills. Other routes of administration of hormones are available, such as trans-dermal patches, estrogen gels, and vaginal creams and rings. Many of the alternative forms offer effective treatment for the symptoms of menopause, such as hot flashes and vaginal dryness.

There is also evidence to suggest that transdermal estrogen patches have beneficial effects on blood lipids, cholesterol, and bone; although many of these benefits are reduced as compared to hormones administered orally. For example, transdermal and oral administration of estrogen both decrease LDL cholesterol, but transdermal administration does not appear to increase HDL levels as oral administration does. Several studies have demonstrated transdermal products to benefit bone density and bone metabolism comparable to oral therapy (33, 34, 35) .

If estrogen-containing vaginal creams and rings are used, the amount of estrogen that enters the blood stream depends on the types of hormone and the dose. Generally, vaginal administration of hormones will result in lower levels of circulating hormones compared to an equivalent oral dose. Because the vaginal epithelium will respond to very small doses of estrogen, low-dose estrogen-containing creams can be used to correct vaginal atrophy. Vaginal estrogen therapy does not appear to protect against bone loss or cardiovascular disease (33, 34).

13. Are there any alternatives for women who choose not to take HRT?

Most women will eventually need to make decisions about whether to take HRT and, if so, for how long. Although hormone replacement therapy can have beneficial effects, there are several health concerns associated with it, and many women may not feel that HRT is a good choice for them.

There are several non-hormonal measures that may prevent osteoporosis and cardiovascular disease. Studies have shown a decrease in the incidence of osteoporosis and cardiovascular disease with modifications in diet and lifestyle, such as avoidance of smoking and regular exercise (20). In addition, non-hormonal prescription drugs, such as statins, are available to lower blood cholesterol (37); others are available to slow bone loss. Calcium and vitamin D supplements are also recommended by some health professionals as a means of preventing osteoporosis (38).

Raloxifene, a hormonal drug approved for prevention of osteoporosis, offers another choice for women (39).

Many women find relief from short-term menopause-related changes with non-prescription remedies, such as estrogen-containing foods (soy products, whole-grain cereal, seeds, certain fruits and vegetables) and creams, certain herbs such as black cohosh, and vitamin E and vitamin B complexes. Researchers are studying the safety and efficacy of these therapies (38). Local therapy is available for vaginal dryness and urinary bladder conditions.

Short-term menopause-related changes may resolve on their own and frequently require no therapy at all.

14. What still needs to be done?

The risk-benefit ratio of HRT is still being debated. Several studies are under way to help women make a more educated and informed choice about whether HRT is right for them. The Women's Health Initiative (WHI), sponsored by the National, Heart, Lung, and Blood Institute, focuses on strategies for preventing heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women. Data from this national long-term health study will be available in seven to10 years (40).

One component of the study is a randomized trial examining the effect of ERT and estrogens combined with progestins on the prevention of heart disease and osteoporosis. Increases in breast cancer risk will also be assessed. Other parts of the study will evaluate the effect of a diet low in fats and high in fruits, vegetables, and grains on the prevention of breast cancer, colorectal cancer, and heart disease as well as the effect of calcium and vitamin D supplements on the prevention of osteoporosis-related fractures.

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