Postmenopausal hormone therapy

DEFINING MENOPAUSE — With the onset of menopause, a woman's body stops making estrogen and progesterone. Estrogen and progesterone are the female hormones produced by the ovaries that prepare the uterus for possible pregnancy. Prior to menopause, (which usually occurs between the ages of 45 and 55), many women notice that their periods start to occur more frequently (as often as every 21 days), although periods eventually become infrequent. This time of "transition," called perimenopause, can last for several years until menopause, when periods stop altogether.

The average age of menopause is between 50 and 51 years, although some women experience unusually early menopause (before age 40) due to surgical removal of the uterus or both ovaries, chemotherapy, or radiation therapy. However, most cases of early menopause are unexplained.

Hot flashes — Hot flashes (or hot flushes) occur because of a fall in estrogen levels. Hot flashes often begin several years before menopause and continue for several years after menopause. They are far more common at night, and can disrupt sleep. Therefore, many women also experience symptoms related to sleep-deprivation, such as fatigue, irritability, difficulty concentrating, and mood swings.

Vaginal and urinary symptoms — Many women begin to experience vaginal dryness or urinary symptoms, both of which are related to estrogen deficiency. Estrogen is the most effective treatment available for hot flashes, vaginal dryness, and urinary symptoms.

Estrogen has important effects on many other organs, such as the brain, skin, blood vessels, heart, bone, and breast. Of particular importance are the effects of estrogen on bone and possibly cardiovascular (heart) health. Without estrogen, the body is at greater risk of developing osteoporosis, a disease in which bones lose calcium and become more susceptible to fracture. In addition, the risk of heart disease in women increases after menopause, although taking estrogen (hormone replacement therapy) has not been shown to prevent heart disease.

HORMONE REPLACEMENT THERAPY — Estrogen replacement therapy, also called ERT, is a way for a postmenopausal woman to replace the estrogen her body is no longer making. While it does not make her fertile again, it does eliminate many of the symptoms of menopause. Women with a uterus who take estrogen must also take a progesterone-like hormone (called progestins) to eliminate the risk of uterine (endometrial) cancer. The term hormone replacement therapy (HRT) is used when estrogen and progestin are given together.

HISTORY OF HRT USE — Estrogen first became popular in the 1960's for the treatment of hot flushes. At that time, it was also thought that estrogen helped to preserve a woman's youthful appearance. Early on, high doses of estrogen were given (as an example, 2.5 mg of conjugated estrogens compared to the standard 0.625 mg dose that is currently used). Since then, the regimens and the reasons for taking it have changed. Taking estrogen alone results in an increased risk of endometrial cancer (also known as uterine cancer). Adding a progestin to estrogen can prevent the increased endometrial cancer risk. Therefore, by the mid-1980s, progestins were routinely added to estrogen replacement therapy (in any woman with an intact uterus, ie, women who had not undergone a hysterectomy). Many studies showed that taking ERT or HRT could prevent the bone loss that occurs after menopause, which can lead to osteoporosis and its fractures. Over 30 studies suggested that estrogen was an important therapy for preventing or reducing the risk of coronary heart disease (CHD). In fact, it appeared that women taking estrogen reduced their risk of a first heart attack by 50 percent. In addition, estrogen appeared to reduce recurrent events in women who already had coronary disease. Because of the osteoporosis and CHD studies, ERT and HRT began to be prescribed for the prevention of both diseases, which meant giving it long-term (more than five years). Breast cancer studies began to indicate that taking ERT more than 5 years increased the risk of breast cancer. Clinical trials, (studies in which women are randomly assigned to receive active treatment or placebo), did not agree with the earlier studies. The Women's Health Initiative (WHI) and the HERS trials (of combined estrogen-progestin therapy) demonstrated that HRT did not prevent heart disease, and in fact, might increase risk. The WHI trial of combined estrogen-progestin therapy did show an increased risk of breast cancer, but there was no increased risk of breast cancer in women who took estrogen alone [1].

One possible explanation for the conflicting results between the observational studies and clinical trials, is that the observational studies had a problem with "healthy user bias". This means that the healthiest women (ie. those who were less apt to have a heart attack), were more likely to be started on estrogen by their physicians. Therefore, it is possible that estrogen's beneficial effect on the heart was more related to the underlying health of the women taking it, rather than the medication itself.

WOMEN'S HEALTH INITIATIVE — The Women's Health Initiative (WHI) is a set of clinical trials that includes two HRT trials. The WHI studied healthy postmenopausal women aged 50 to 79 years, and the study was scheduled to be completed in 2005. However, one component of the WHI (continuous, combined conjugated estrogen (CEE 0.625 mg/day) and medroxyprogesterone acetate (MPA 2.5 mg/day) versus placebo in over 16,000 women) was discontinued in 2002 because of an increased risk of coronary heart disease, breast cancer, stroke, and venous thromboembolism (blood clots in the leg or lung) over an average follow-up of 5.2 years [2]. Although there was reduction in risk of osteoporotic fractures and colon cancer, there was concern that the risks of combined estrogen-progestin may outweigh the benefits.

The WHI trial of unopposed estrogen (CEE 0.625 mg/day) versus placebo in women who had undergone hysterectomy (and therefore did not require a progestin) was also discontinued (early 2004) because of a small increase in stroke risk (but no increase in CHD or breast cancer risk) [1].

Only one type of estrogen (CEE 0.625 mg) and one type of progestin (MPA 2.5 mg) treatment were studied in the WHI brand names Premarin (unopposed estrogen) and Prempro (estrogen combined with progestin). Although there are theoretical reasons to believe that other types of estrogen and progestin, different routes of administration (skin patch) or lower doses might be safer, to date, there are no studies to demonstrate that this is true.

The results of the WHI were as follows [2]:

Coronary heart disease — The rate of coronary events such as heart attacks was 24 percent higher in the women taking HRT compared to those taking placebo. This seems like a large increase in risk, but the increase for an individual woman is low. As an example, on average there were 39 CHD events per year per 10,000 women versus 33 events per 10,000 women taking placebo (ie, an additional 6 events per 10,000 women per year).

The difference in coronary events developed within the first year of the study. The risk persisted in years two through five of the study, but the highest risk was in the first year. Taking a daily aspirin did not seem to reduce the risk.

In contrast, the WHI trial of unopposed estrogen did not observe an increase in CHD risk. In the younger women in the trial (ages 50-59), a possible protective effect was seen with estrogen (although this was not significant).

The WHI investigators subsequently reported that women ages 50 to 59 years at baseline, who had been menopausal for less than 10 years, did not have an increased risk of heart disease. The excess risk was only seen in older women in the trial. This was true for both the combined estrogen-progestin trial and the unopposed estrogen trial.

Prevention of CHD after a heart attack was evaluated in the HERS trials with 2763 postmenopausal women [3]. After nearly 7 years of follow-up, continuous estrogen-progestin therapy did not reduce the risk of CHD events in women with established CHD.

Stroke — The rate of stroke was increased with combined estrogen-progestin. On average per year, there were 29 strokes in the treatment group versus 21 events in the placebo group per 10,000 women (8 additional cases per 10,000 women per year). Most of the increase in risk was due to nonfatal strokes, and the increase did not appear until year two of the study (but persisted through year five). A very similar pattern of risk was seen in the trial of unopposed estrogen [1]. (See "Patient information: Stroke").

Blood clots — The rate of blood clots (in the leg and lung) increased with combined estrogen-progestin (34 versus 16 per 10,000 women per year; or 18 additional cases per 10,000 women per year). Risk was also increased with unopposed estrogen. (See "Patient information: Venous thrombosis").

Breast cancer — The risk of breast cancer was increased in the WHI trial of combined estrogen-progestin. On average, per year there were 38 cases of breast cancer per 10,000 women versus 30 per 10,000 women (8 additional cases per year per 10,000 women). Similar findings have been noted in a number of observational studies, all of which suggest that the major increase in risk occurs after taking estrogen-progestin for four or five years. In addition, the WHI reported that women taking combined estrogen-progestin were more likely to have an abnormal mammogram. However, the majority of the abnormal mammograms were requests to return for additional views.

The results of the trial of unopposed estrogen were quite surprising, because no increase of breast cancer was seen. In fact, a possible lower risk was seen, but this was not quite significant. The fact that an increase in breast cancer risk was seen with combined hormone therapy, but not with unopposed estrogen, suggests that the progestin component is a very important factor in the risk of developing breast cancer. (See "Patient information: Postmenopausal hormone therapy and breast cancer").

Osteoporotic fracture — The risk of osteoporotic fracture was reduced at the hip and spine in both the trial of combined estrogen-progestin and the trial of unopposed estrogen. On average, per year there were 5 fewer hip fractures per 10,000 women in the HRT versus placebo group. (See "Patient information: Osteoporosis prevention and treatment").

Colorectal cancer — The risk of colorectal cancer was reduced (6 fewer colorectal cancers per 10,000 women per year) in the trial of combined estrogen-progestin versus placebo group. This benefit was not seen in the trial of unopposed estrogen. (See "Patient information: Screening for colon cancer").

Cognitive function and dementia — Although it was thought that estrogen could preserve cognitive function and prevent dementia, data from the WHI do not support this. No significant improvement in overall cognitive function was seen with combined estrogen-progestin therapy compared with placebo. It is still possible, however, that there are benefits for certain specific types of cognitive function, although this is not proven. The impact of unopposed estrogen, or taking HRT in the early postmenopausal years is not known.

In addition, combined estrogen-progestin therapy did not prevent dementia. To the contrary, an increased risk was seen (approximately 23 additional cases of dementia per 10,000 women per year). It is not known why dementia risk was higher with hormone therapy, but one possible explanation is an increased risk of multiple small strokes (which predisposes women to dementia). Similar results were reported in the unopposed estrogen trial. The effect of taking HRT in the early menopausal years on the risk of later dementia is not known, although many early studies suggest that it is early, rather than late, exposure to estrogen is important for later cognitive function.

Endometrial hyperplasia and cancer — Studies have found that postmenopausal women with a uterus who are treated with estrogen alone increase their risk of endometrial cancer and hyperplasia (a precursor to cancer). Within one year, endometrial hyperplasia can be found in 20 to 50 percent of women receiving estrogen alone. The risk can be even greater if very high doses are used or if the unopposed estrogen is continued for many years. Even when women discontinue the estrogen, the endometrial cancer risk persists for approximately five years.

In the WHI, only women without a uterus received unopposed estrogen. In women with a uterus who received combined estrogen-progestin therapy, there was no increased risk of endometrial hyperplasia or cancer.

Absolute risk of an adverse event — It should be emphasized that the absolute risk of an adverse event occurring in an individual on the estrogen-progestin regimen in the WHI was extremely low (19 additional events per year per 10,000 women with HRT compared to placebo).

In the trial of unopposed estrogen, it was calculated that overall risks and benefits would be equal (not taking into account the effect that estrogen has on hot flashes).

Most now agree that using either unopposed estrogen or combined estrogen-progestin therapy for symptom relief in young postmenopausal women in a safe and reasonable option.

OTHER RISKS — There are many HRT studies in addition to the WHI that provide other information about breast cancer. In addition, there are other known risks of HRT such as gallbladder disease that were not addressed in the WHI report.

Other breast cancer issues — The degree of increase in breast cancer risk due to estrogen is often misinterpreted. It is most important for a woman to understand the absolute risk that she will get breast cancer because she takes estrogen. It has been calculated that for a 50-year-old woman taking estrogen, there is a 1 in 100 chance that she will develop breast cancer over a 10-year period that would not have developed without estrogen. This estimate would be slightly higher (eg, 1.5 in 100) for a woman over 65 years of age.

Many studies have reported that if breast cancer does occur during estrogen therapy, it is biologically less aggressive, and survival rates are better than when breast cancer occurs in women who were not taking estrogen. However, in the WHI combined estrogen-progestin trial, women on hormones had tumors that were slightly larger and more likely to have spread to the lymph nodes. As mentioned above, no increase in breast cancer risk was seen in the trial of unopposed estrogen.

Gallbladder disease — There is considerable evidence that estrogen therapy, especially in pill form, is associated with an increased risk of gallbladder disease. The risk of cholecystectomy, (removal of the gallbladder), increases the longer a woman uses hormone therapy and the higher the dose of estrogen used. The risk decreases substantially within one to three years after a woman discontinues hormone therapy.

OTHER BENEFITS — In addition to easing the symptoms of menopause, ER/HRT has many other positive effects.

Menopausal symptoms — Estrogen is the most effective treatment available for symptoms such as hot flashes, urinary symptoms, and vaginal atrophy (atrophic vaginitis), a condition in which the vagina can become dry, resulting in pain with intercourse.

Quality of life — Women with severe menopausal symptoms often describe a dramatic improvement in their quality of life when they are treated with estrogen. This is due to relief of hot flushes and restoration of normal sleep.

Urinary tract infection — Estrogen has been found to decrease the frequency of urinary tract infections, possibly by normalizing the microorganisms present in the vagina. It does not help the symptoms of urinary incontinence. (See "Patient information: Urinary tract infection in adults").

Diabetes mellitus — The WHI reported that HRT appears to reduce the risk of type 2 diabetes mellitus (adult onset diabetes). However, because of the other risks of HRT, this effect is insufficient to recommend HRT for routine diabetes prevention in postmenopausal women. (See "Patient information: Diabetes mellitus, type 2").

Depression — Estrogen may improve mood and decrease depression in some menopausal women. One study showed that estrogen plus progestin was effective in perimenopausal women with depression. (See "Patient information: Depression in adults").

WHO SHOULD TAKE HRT?— Data from the WHI and the HERS trials have led to changes in our recommendations for hormone therapy [2,3]. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. Unopposed estrogen increases the risk of stroke, but overall, its benefits seem equal to its risks. As a result, the main reason to take hormone therapy at present is to control menopausal symptoms.

Menopausal symptoms — Estrogen or combined estrogen-progestin therapy remains the gold standard for relief of menopausal symptoms, and therefore is a reasonable option for most postmenopausal women, with the exception of those with a history of breast cancer, CHD, a previous blood clot or stroke, or those at high risk for these complications. In otherwise healthy women, the absolute risk of an adverse event is extremely low. Most experts agree that hormone therapy is safe and reasonable for healthy postmenopausal women who need to take it to relieve symptoms. When it is used, is should be taken for the shortest period of time possible.

Administration of estrogen short-term is not associated with an increased risk of breast cancer, but endometrial hyperplasia and cancer can occur after as little as six months of unopposed estrogen therapy; as a result, a progestin must be added in those women who have not had a hysterectomy.

In women being treated for symptoms, the goal is to eventually taper and stop the estrogen (unless there is a compelling reason to continue it long-term). After the planned treatment interval, the estrogen should be discontinued gradually, as an example, by omitting one pill per week, to minimize recurrence of the menopausal symptoms.

Low-dose oral contraceptives — A low-estrogen oral contraceptive (20 µg of ethinyl estradiol) remains an appropriate treatment for perimenopausal women who seek relief of menopausal symptoms. Most of these women are between the ages of 40 and 50 years and are still candidates for oral contraception. For them, an oral contraceptive pill containing 20 µg of ethinyl estradiol provides symptomatic relief, contraception, and sometimes better bleeding control than conventional estrogen-progestin therapy. (See "Patient information: Hormonal methods of birth control").

Dose of estrogen — It is possible that lower doses of estrogen may be safer than estrogen, while still effectively treating menopausal symptoms. As an example, conjugated estrogens (0.3 mg) or the equivalent dose of other estrogens (estradiol, estrogen patch) have been shown in some, but not all studies to relieve symptoms and prevent bone loss. But it is not yet known whether lower doses of estrogen or different HRT preparations are safer with regards to breast cancer and cardiovascular risks. Therefore, it is safest to assume that other preparations carry the same risk.

Long-term estrogen therapy — Only a minority of women who are unable to successfully discontinue estrogen without persistent symptoms should consider long-term estrogen therapy. If HRT is resumed, the lowest dose possible should be used, and plans should be made to try another taper at a later date. It is important that the breast cancer and cardiovascular risks are discussed in detail with these women.

TYPES OF ESTROGEN — Estrogen can be taken as a pill (orally), or absorbed through the skin from a patch (transdermally), or inserted into the vagina.

Estrogen pill — There are many forms of estrogen pills. The most commonly used preparation, called Premarin, is made from pregnant mares' urine. Many other preparations are derived from plant sources, such as soy and yams. While there is no evidence that plant-derived estrogens work better or are safer than Premarin, many women prefer them.

Sometimes the dose of estrogen is large enough to protect bones, but not to completely eliminate menopausal symptoms. When these symptoms occur, a larger dose may be given for a year or two, but then the dose is usually reduced.

Besides Premarin, other brands of estrogen include: Cenestin, Estratab, Menest, Ogen, Estrace, and Gynediol. While these preparations vary in their potency and dose amounts, they are all effective.

Estrogen patch — There are many brands of estrogen patches. Those available in the United States include: Estraderm, Climara, Vivelle, FemPatch, and Alora. Some patches need to be replaced every few days, others once a week.

If an equivalent dose is given, transdermal estrogen is just as effective as oral estrogens in increasing bone density and in treating menopausal symptoms. But unlike oral estrogen, it has not been shown to have a beneficial effect on cholesterol levels.

Vaginal estrogen — Vaginal estrogen is available as a cream, vaginal ring, or vaginal tablet. Estrogen cream is inserted into the vagina using an applicator once a day for two to three weeks. After this, the frequency may be reduced to one or two times weekly. The estrogen vaginal tablet (Vagifem®) is given on a similar schedule.

The vaginal ring, called Estring, is a flexible plastic ring. It is inserted once every three months and does not need to be removed during intercourse or bathing. Estring may be preferred by women who have trouble using vaginal cream on a regular basis, or in women with reproductive organs that may be sagging, called prolapse, who would benefit from additional support.

Vaginal estrogen is an excellent choice for women who want to control vaginal dryness or prevent frequent urinary tract infections. Unlike the estrogen in pills and patches, very little vaginal estrogen is absorbed by the rest of the body. As a result, vaginal estrogen does not have the other positive or negative effects.

There is one vaginal estrogen product for postmenopausal women that contains a higher dose of estrogen (Femring®). This ring contains a higher dose of estrogen that is absorbed into the bloodstream to relieve hot flashes. We do not recommend Femring for women who need vaginal estrogen to relieve vaginal dryness or urinary symptoms.

TYPES OF PROGESTIN — As noted above, progestins are now routinely added to estrogen for any woman with a uterus. The most commonly prescribed progestin is medroxyprogesterone acetate, available in pill form under the brand names Provera, Cycrin, or Amen. There are other progestin preparations, like those used in oral contraceptives, but none have obvious advantages over medroxyprogesterone. A natural progesterone, called Prometrium®, may be a good alternative for women who cannot tolerate medroxyprogesterone. In addition, natural progesterone has no negative effect on lipids, and therefore is a good choice in women with underlying high cholesterol levels.

ALTERNATIVES TO ERT/HRT — Not all women are able or willing to take estrogen replacement, and alternative therapies are available. These are discussed in detail elsewhere (See "Patient information: Alternatives to postmenopausal hormone therapy").

BREAST CANCER AND ESTROGEN — Although women with breast cancer often experience early menopause due to adjuvant chemotherapy, and may have vasomotor symptoms due to tamoxifen therapy, estrogen therapy (by mouth or patch) is generally not recommended.

In a study called the HABITS trial, 434 women with breast cancer were randomly assigned to receive two years of HRT (estrogen alone or with progestin depending upon hysterectomy status) or no hormones [4]. After 2 years of follow-up, women in the estrogen groups were at least three times more likely to have a recurrence than women who did not take hormones. Based upon the excessive risk in the hormone group, the study was terminated in December 2003.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Hormone Foundation

(www.hormone.org/public/menopause.cfm, available in English and Spanish)


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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Anderson, GL, Limacher, M, Assaf, AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1701.
2. Rossouw, JE, Anderson, GL, Prentice, RL, et al. 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.
3. Grady, D, Herrington, D, Bittner, V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49.
4. Holmberg, L, Anderson, H. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363:453.