Questions and Answers: Use of Hormones After Menopause

Updated: 07/16/2002

1. 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. Women who have surgery to remove both of their ovaries (an operation called bilateral oophorectomy) experience "surgical menopause," the immediate cessation of ovarian hormone production and menstruation.

In postmenopausal women, estrogen levels are about one-tenth the level in premenopausal women and progesterone is nearly absent. The low levels of estrogen after menopause are produced by the adrenal glands and fat cells. Estrogen usage, with or without progestin, approximately doubles the estrogen level of a postmenopausal woman. Therefore, even with hormone treatment, estrogen and progesterone levels of a postmenopausal woman do not reach the natural levels of a premenopausal woman.

2. What hormones may be used after menopause?

Postmenopausal hormone use usually involves treatment with either estrogen alone or in combination with progestin to compensate for the decrease in natural hormones that occurs at menopause. Estrogen is a natural hormone manufactured primarily by the ovaries. It is involved in the development and maintenance of secondary sex characteristics such as breasts in females and affects many aspects of women's physical and emotional health. Progestins are preparations that have effects similar to those of the natural hormone progesterone, which is primarily responsible for regulating the reproductive cycle. Among women who use postmenopausal hormones, women who have had their uterus removed use estrogen alone, whereas women with a uterus take a combination of estrogen plus progestin.

About 8 million women in the United States take estrogen alone and about 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 postmenopausal hormones for at least one month and 20 percent continued use for five or more years (1).

3. Why are hormones used after menopause?

Doctors may recommend using estrogen alone (if a woman does not have a uterus) or in combination with progestin to counter some of the possible effects of natural or surgical menopause on a woman's health and quality of life. Symptoms of menopause may include hot flashes, night sweats, sleeplessness, and vaginal dryness.

Hormones have also traditionally been prescribed to prevent some long-term conditions that are more common in women after menopause, such as osteoporosis and coronary heart disease (CHD). However, recent results from the Women's Health Initiative (WHI), a large randomized trial sponsored by the National Institutes of Health (NIH), have shown that overall, the risks of long-term estrogen with progestin outweigh the benefits. According to these results, estrogen with progestin increases the risk of both cardiovascular disease and breast cancer. Women should discuss risks and benefits of combined hormone use with their health care provider before selecting hormones for use in preventing osteoporosis (2). The results for use of estrogen alone are not yet known.

4. What are the effects of postmenopausal hormone use on the uterus?

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 estrogen (3). However, some studies have shown increases in endometrial cancer risk with the combined regimens if progestins are used for less than ten days per month (4, 5).

Generally, standard postmenopausal hormones for women who have undergone hysterectomy (surgical removal of uterus) has been estrogen alone, whereas women who have not undergone this procedure have been given the estrogen-progestin combination.

5. What is known about the effects of postmenopausal hormones on heart disease?

The estrogen and progestin component of the Women's Health Initiative, which included over 16,000 women, compared two groups of healthy women (no prior history of heart disease), one using estrogen with progestin and one taking a placebo. In this study, combined estrogen and progestin was associated with a 22 percent increased risk of cardiovascular disease. The incidence of heart attacks increased 29 percent among women taking estrogen and progestin, as compared to the group of women on placebo (2). These effects became apparent after an average of 5.2 years of follow-up.

Another randomized trial, the Heart and Estrogen/progestin Replacement Study, recently concluded that estrogen in combination with progestin has no beneficial effects on the heart. Although earlier results from this study had suggested such benefits might exist, longer follow-up (6.8 years) found no overall reduction in the risk of heart attacks and coronary deaths with use of estrogen and progestin (6).

Some observational studies in which women reported whether they had used postmenopausal hormones have found evidence of a protective effect against CHD with use of estrogen alone (7). Most of the participants in these studies were healthy women at low risk for CHD. The WHI is continuing to investigate the potential benefits and risks of estrogen therapy on the heart in a randomized clinical trial that is expected to conclude in 2005.

6. What is known about the effects of postmenopausal hormones on bone health?

Postmenopausal osteoporosis is characterized by decreased bone mass, deterioration of bone tissue, and increased bone fragility, making bone fractures of great concern. Low levels of estrogen are a risk factor for osteoporosis in women.

Estrogen alone and estrogen combined with progestin have been shown to protect against osteoporosis. Definitive data from a recent large clinical trial support the ability of estrogen with progestin to prevent fractures at the hip, vertebrae, and other sites (2). 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 ages 75 to 80 years old (8, 9). Women who take estrogen to maintain bone density must continue taking estrogen because its beneficial effects on bone health disappear after hormone use is discontinued.

7. How does postmenopausal hormone use affect breast cancer risk and survival?

The estrogen and progestin component of the Women's Health Initiative concluded definitively in 2002 that combined estrogen and progestin therapy increases the risk of invasive breast cancer. After an average of five years of follow-up for each of more than 16,000 women in the study, the study found a 26 percent increase in breast cancer risk as compared to women taking placebo (2).

After five years of follow-up, the WHI study had found no indication of an increased incidence of breast cancer in the group of 11,000 trial participants taking estrogen alone (2). This clinical trial of estrogen vs. placebo is continuing. Observational studies, however, do indicate an increase in risk among women taking estrogen alone. 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 postmenopausal hormones for five years or longer. Most of the women included in this re-analysis were on estrogen alone. In this study, the increase in risk was seen not only in current users, but also in women who stopped therapy some time in the previous four years. No increased risk was seen in women who had stopped therapy more than four years earlier (10).

While observational studies indicate that both groups of hormone users have a higher risk of breast cancer than non-users, the risk appears to be greater among women using combined therapy than in women using estrogen alone (11, 12). One recent observational study found that risk increased with longer duration of hormone use and returned to the risk of non-users five or more years after use was stopped (12).

For women diagnosed with breast cancer, previous use of estrogen alone may have survival benefits. One study of breast cancer patients showed that users of estrogen had lower mortality rates from breast cancer than non-users. Most of these patients stopped using estrogen at the time of diagnosis. However, this protective effect diminished with time (15).

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

A recent study that followed 44,241 postmenopausal women for approximately 20 years concluded that estrogen use is associated with an increased risk of ovarian cancer. In this study, women who used estrogen alone for 10-19 years were twice as likely to develop ovarian cancer than women who did not use postmenopausal hormones. For women who used estrogen for 20 or more years, the risk of ovarian cancer increased to three times that of women who did not use postmenopausal hormones (Lacey). Another recent large 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 estrogens for 10 or more years (16).

Because most studies have followed women using estrogen alone, there are currently not enough data to assess the potential effects of the estrogen-progestin combination on ovarian cancer (14). The above study of 44,241 postmenopausal women found that those who used estrogen in combination with progestin were not at increased risk of ovarian cancer, but the number of women in the study that had used estrogen plus progestin was small. More data are needed to determine whether estrogen-progestin has any effect on ovarian cancer risk (Lacey). One recent 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 (15). More research is needed to clarify the relationship between postmenopausal hormone use and the risk of ovarian cancer in postmenopausal women.

9. What are the mortality benefits associated with postmenopausal hormone use?

Studies have shown a slightly lower total mortality rate among postmenopausal women using hormones. However, the WHI trial of estrogen plus progestin found no change in overall mortality associated with hormone use (2).

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

Estrogen is very effective for treating menopausal symptoms such as hot flashes, sleeplessness, and vaginal dryness. Estrogen does not appear to be an effective treatment for these symptoms when they occur in older women (18).

Postmenopausal hormones may improve mood and psychological well-being in women who have hot flashes and sleeplessness during menopause, but should not be used to treat the symptoms of major depression. There are other reports that estrogen prevents memory loss, delays the onset of Alzheimer's disease, and improves urinary incontinence. However, there are no convincing clinical trial data to support these claims (19).

After five years of follow-up of women taking combined therapy, the Women's Health Initiative reported a 37 percent reduction in colorectal cancer cases compared to women on placebo. Further studies will be needed to confirm this finding (2).

Women who use estrogen plus progestin are at increased risk for blood clots (20, 21), gallbladder disease (21, 22, 23), and stroke (2, 24). Increased cases of blood clots in the lung (pulmonary embolisms) and inflammation of veins (thrombophlebitis) have also been reported with hormone use (25).

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

One of estrogen's primary roles is to promote the growth of cells in the breast and uterus. For this reason, there is concern that use of postmenopausal estrogen after cancer may promote further tumor growth. However, the safety of replacing women's estrogens after endometrial and breast cancer remains uncertain (26).

Only a small amount of research has been done to look at the risks associated with postmenopausal hormones for women who have a history of endometrial cancer. A few small studies have found no evidence that hormone use adversely influences survival and/or recurrence of the disease in these women (27). 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 (Estrogen Replacement Therapy 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.

One study of breast cancer patients reported no increase in recurrence or mortality among women who continued hormone use following their diagnosis (28). Most of the women in this study were using estrogen alone.

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 transdermal patches, estrogen gels, and vaginal creams and rings. These forms of estrogen are all equally effective methods of treating 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. Several studies have found the benefit of transdermal products on bone density and bone metabolism to be comparable to that of oral therapy (29, 30, 31).

The amount of estrogen that enters the blood stream from estrogen-containing vaginal creams and rings depends on the types of hormones 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 (29, 30).

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

Although postmenopausal hormones can have short-term beneficial effects, there are several health concerns associated with it, and many women may not feel that hormones are a good choice for them. Women should discuss with their health care provider whether to take postmenopausal hormones and what alternatives may be appropriate for them.

All women can adopt a healthy lifestyle, such as not smoking, regular exercise, and good nutrition (32). In addition, other prescription drugs, such as statins or beta-blockers, are available to lower blood lipid levels or blood pressure levels (33).

A healthy lifestyle can also help decrease a woman's risk of bone loss. In addition, health professionals also recommend calcium and vitamin D supplements as a means of preventing osteoporosis (34). Other drugs, such as raloxifene, tibolone, alendronate, and risedronate have been shown to prevent bone loss. These drugs increasingly are becoming the treatment of choice for osteoporosis in many postmenopausal women. (35). The investigational drug PTH (parathyroid hormone) is another prevention approach being evaluated in clinical trials.

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 (34). Local non-hormonal 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 research still needs to be done?

Several studies are under way to help women make a more educated and informed choice about whether postmenopausal hormones are right for them. In particular, the risk-benefit ratio of estrogen alone for women who have had a hysterectomy is still being evaluated.

The Women's Health Initiative (2) focuses on strategies for preventing heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women (36). While the component of the study focusing on the effects of estrogens combined with progestins has closed, another part of WHI with 11,000 participants is focusing on the effect of estrogen alone on heart disease and osteoporosis and is expected to continue until 2005. The impact of estrogen alone on breast cancer risk will also be assessed.

Other parts of the WHI 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.

References

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(19) International Position Paper on Women's Health and Menopause: A Compreshensive Approach. Best Clinical Practices.2002;Chapter 13.

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Additional References

Brekwoldt M, Keck C, Karck U. Benefits and risks of hormone replacement therapy (HRT). J Steroid Biochem Mol Bio 1995;53(1-6):205-8.

Brinton LA, Schairer C. Postmenopausal hormone-replacement therapy: time for reappraisal? N Engl J Med 1997;336(25):1821-1822.

Bush TL, Whiteman MK. Hormone replacement therapy and risk of breast cancer. Editorial. JAMA 1999;281(22):2140-2141.

Oates MB, McGhan WF, Smith MD. Hormone replacement therapy: a review of the risk versus benefit-Part II. Med Interface 1997;10(1):108-14.

Colditz G, Rosner B, for the Nurses' Health Study Research Group. Use of estrogen plus progestin is associated with greater increase in breast cancer risk than estrogen alone. Am J Epidemiol 1998;147(suppl):84S.

Persson I, Weiderpass E, Bergvist L, et al. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control 1999;10(4):253-260.