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)
[1-4]
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.
Sunday, October 14, 2007
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)
[1-4]
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.
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)
[1-4]
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.
Alternatives to postmenopausal hormone therapy
INTRODUCTION — During a woman's reproductive years, the body produces a variety of hormones, including estrogen. Estrogen is important for normal menstrual periods and fertility, and it promotes bone strength. Estrogen levels fall at the time of menopause, causing well-known symptoms such as hot flashes. This fall in estrogen increases a woman's risk of osteoporosis and heart disease.
Hormone replacement therapy (HRT) is the term used for estrogen or for estrogen plus progestin treatment after menopause. Progestins are drugs that act like the female hormone progesterone, and they are added to the estrogen to prevent uterine cancer (which can occur if estrogen alone is given to women with a uterus). HRT is an effective option for treating the symptoms of menopause, and it helps prevent osteoporosis.
STUDIES OF HORMONE REPLACEMENT — Previously, scientists thought HRT would reduce the risk of heart disease in postmenopausal women. However, data from large studies such as the Women's Health Initiative (WHI) and HERS trials have shown that combined estrogen-progestin therapy does not reduce the risk of heart disease. In fact, estrogen plus progesterone might increase risk slightly [1,2].
More recent studies, however, suggest that HRT might protect against heart disease in younger postmenopausal women (ie, those 50 to 59 years of age). In the WHI trial of estrogen alone, there was no increased risk of heart disease but the risk of stroke was increased.
The WHI also reported an increased risk of breast cancer with combined estrogen-progestin (similar to that seen in previous studies), and an increase in stroke and blood clots (in the leg and lung). On the other hand, a decrease in the risk of colon cancer and fractures (due to osteoporosis) was also seen. However, the investigators concluded that the risks of HRT may outweigh its benefits in many women.
The results of the WHI trial of unopposed estrogen were quite different. While an increase in strokes and blood clots was seen, there was no increase in breast cancer risk. (See "Patient information: Postmenopausal hormone therapy").
Data from the WHI and the HERS trials have led to changes in our recommendations for estrogen therapy. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer, while unopposed estrogen appears to increase stroke risk; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. As a result, the primary indication for estrogen therapy at present is for control of menopausal symptoms. For long-term prevention of heart disease and osteoporosis, most women need to consider lifestyle interventions and medications other than estrogen.
A number of alternatives are now available to control menopausal symptoms. This is particularly important for women who have had breast cancer, because hormone therapy appears to increase the risk of recurrence. (See "Patient information: Postmenopausal hormone therapy").
PREVENTING AND TREATING OSTEOPOROSIS — When estrogen levels fall, bone density (strength) starts to decline, and, over time, a woman can develop osteoporosis and even fractures. Your doctor may recommend bone mineral density tests (ie, DEXA scan) to monitor for early bone loss. Several alternatives to HRT can help keep bones strong and even partially reverse osteoporosis, but effective treatment for established osteoporosis usually requires the combination of changes in diet, lifestyle, and medication. (See "Patient information: Osteoporosis causes, diagnosis, and screening" and see "Patient information: Osteoporosis prevention and treatment").
Calcium — Calcium is an essential component of bones, and calcium from foods we eat can help strengthen bones. However, calcium alone cannot always prevent osteoporosis. All postmenopausal women need 1500 mg of calcium each day. Most women will need to eat a well-balanced diet and take a daily supplement that contains 1000 mg of calcium, usually in the form of calcium carbonate, calcium citrate, or an equivalent calcium compound. A list of calcium-rich foods and guidelines for choosing calcium supplements (show figure 1). (See "Patient information: Calcium for bone health").
Vitamin D — Vitamin D helps the body absorb calcium and incorporate calcium into bone. It is therefore also important for bone strength. Many older adults, particularly those over 70 years, have vitamin D deficiencies. Postmenopausal women under the age of 70 years should get at least 400 IU of vitamin D each day in their diet or with a vitamin supplement. Women over 70 years should take 800 IU of vitamin D. Some calcium supplements include vitamin D; patients should read the label to know the amount included.
Exercise — Bones remain stronger when they are used in day-to-day activities, and inactivity increases the rate of postmenopausal bone loss. At least 30 minutes of weight-bearing exercise three times a week can reduce this loss. Weight-bearing exercise includes activities such as walking, aerobics, or tennis, but does not include bicycling or swimming.
Medications — Several medications, such as alendronate, risedronate, ibandronate, zoledronic acid, tamoxifen, and raloxifene can help prevent or even reverse osteoporosis by boosting bone density. These medications can even benefit women who have already suffered fractures. Women taking these medications should continue to take calcium and to follow other measures that promote bone strength. A new drug, human parathyroid hormone (Forteo), given by daily injection under the skin, is now available for the treatment of severe osteoporosis.
Alendronate, risedronate, and ibandronate — Alendronate (Fosamax®), risedronate (Actonel®), and ibandronate (Boniva®) are prescribed for the prevention and treatment of osteoporosis in postmenopausal women. They are able to prevent and reverse bone loss as effectively as estrogen. Women need to take these medications with water 30 minutes before eating in the morning and must sit upright or stand for this time period, to prevent pill-associated irritation of the esophagus (the part of the digestive tract between the mouth and stomach). Women who already have esophageal problems such as heartburn or esophagitis should not take these medications. Preparations are now available that allow patients to take alendronate once weekly and ibandronate once monthly.
Tamoxifen and raloxifene — Tamoxifen (Nolvadex®) is usually prescribed for women with breast cancer. Tamoxifen opposes the action of estrogen in breast tissue, but actually has an estrogen-like effect on bone in post-menopausal women. As a result, tamoxifen increases bone mineral density and decreases the number of bone fractures in postmenopausal women. The most bothersome side effect of tamoxifen is hot flashes. Tamoxifen is usually taken once daily, but is not prescribed for more than five years in women who have had breast cancer. Tamoxifen is also used for prevention of breast cancer in women at high risk. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
Raloxifene (Evista®) is similar to tamoxifen in that it has an anti-estrogen effect on breast tissue and an estrogen-like effect on bone. In contrast to tamoxifen, it does not cause uterine cancer. It is used for the prevention and treatment of osteoporosis, and has been tested for breast cancer prevention in women who are at high risk. Hot flashes are a side effect in some women who take raloxifene.
PREVENTING CARDIOVASCULAR DISEASE — The fall of estrogen concentrations after menopause is associated with an increased risk of developing and dying from cardiovascular disease. Replacing estrogen does not lower this risk in women over 60 years of age. Alternatives to HRT can effectively reduce some of the risk factors associated with cardiovascular disease, such as high cholesterol levels.
Smoking cessation — Quitting smoking is probably the most important change a woman can make to decrease her risk of developing heart disease. Be sure to ask your doctor about methods for successfully quitting. (See "Patient information: Smoking cessation").
Dietary modification — Before prescribing any medication, your doctor may recommend a trial of a low-fat diet to bring cholesterol levels under control. If this approach is successful, medication may not be necessary. (See "Patient information: Diet and health").
Cholesterol-regulating medication — In postmenopausal women with high serum cholesterol levels, medications such as statins (ie, simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin) lower levels of total and low-density-lipoprotein (LDL) cholesterol ("bad" cholesterol). These medications also decrease a woman's risk of heart disease. HRT does not prevent heart disease while the statin drugs have been shown to have this effect. (See "Patient information: High cholesterol and lipids (hyperlipidemia)").
CONTROLLING HOT FLASHES — New alternatives for the treatment of hot flashes have been tested and shown to be effective. None work nearly as well as estrogen, but relief from these agents is about 70 percent as effective as estrogen. No treatment may be necessary since hot flashes typically subside after one to two years, even without treatment, and may not be particularly severe. Some of the treatments that can give partial relief of hot flashes include:
Antidepressants — Venlafaxine (Effexor®), and paroxetine (Paxil®) have been shown to relieve hot flashes. This type of medication is usually used to treat depression, but more recent studies show them to be effective for hot flashes. Venlafaxine has been more extensively studied than the others. Fluoxetine (Prozac®) is also effective. These medications can be tried first in women who cannot take estrogen who suffer with hot flashes . However, side effects can occur with these medications as well. Women taking tamoxifen should be cautioned that paroxetine and sertraline (Zoloft®) interfere with the action of tamoxifen.
Clonidine — Clonidine, a blood pressure lowering drug, helps relieve hot flashes in some women. Clonidine is administered by transdermal skin patch (Duraclon®), oral medication (Catapres®), or a combination of both. Clonidine seems to work well in some patients and to be completely ineffective in others. Only a trial of medication can identify those women who receive benefit. Side effects can range from dry mouth and constipation to dizziness and sedation.
Gabapentin — Gabapentin (Neurontin®) is a drug that is primarily used for the treatment of seizures. Although it has not been as well studied as the SSRIs, it appears to be moderately effective for hot flushes and is well tolerated. Because its main side effect is drowsiness, gabapentin is most effective in reducing early morning awakening which can accompany hot flashes.
Megestrol acetate — Megestrol acetate (Megace®) is a hormone that is sometimes used for women who have had breast cancer. It is nearly as effective as estrogen, but can only be given short-term (for several months). Prolonged use of megestrol acetate can lead to weight gain and serious effects can occur if the medication is stopped abruptly. For this reason, the SSRI class of drugs is used before trying megestrol acetate. Recent studies also demonstrate benefit of an injectable progestin hormone, medroxyprogesterone acetate (Depo-Provera®). Depo-Provera® can be used long-term, though can also have side effects, including weight gain and loss of bone density.
Plant-derived estrogens — Plant-derived estrogens, also called phytoestrogens, sometimes help relieve hot flashes somewhat. Dietary sources of phystoestrogens include soy products. Other phytoestrogens such as ginseng, dong quai, and black cohosh can be purchased at health-food stores. However, these supplements might increase breast cancer risk because they act like estrogen in some tissues of the body. The efficacy of these supplements for hot flashes has not been rigorously proven. The same precautions should be used for these compounds as with HRT in breast cancer survivors.
TREATING VAGINAL DRYNESS — When estrogen production falls, the lining of the vagina thins, leading to vaginal dryness, and sometimes painful sexual intercourse. Several alternatives to estrogen can help control these symptoms. (See "Patient information: Sexual problems in women").
Moisturizers and lubricants — Regular use of vaginal moisturizing agents, such as Replens® or KY Long Lasting®, can help relieve vaginal dryness and irritation. These agents must be used regularly and at times other than before intercourse since they work by moisturizing the vaginal tissues, but can be irritating on direct contact.
Lubricants can prevent pain during sexual intercourse and are used immediately before intercourse. Water-soluble lubricants, such as Astroglide®, are more effective for intercourse than lubricants such as K-Y jelly. Products such as petroleum jelly or hand and body lotions should not be used to relieve vaginal dryness since they can be irritating to the vaginal tissues.
Vaginal estrogens — Estrogen creams, such as Premarin® or Estrace®, can be applied directly to the vagina. When applied in a very low dose, they improve the health of the vaginal tissues without substantially increasing levels of estrogen in the bloodstream. Vaginal estrogen creams are given every day for two to three weeks, and then only once or twice weekly to maintain the effects. They are more effective than moisturizers and lubricants for relieving vaginal symptoms. The lowest dose which is effective should be used. Vaginal estrogen tablets (Vagifem®) and very low-dose vaginal estrogen rings (Estring®) are similarly effective and may be less messy and more convenient than estrogen creams.
Vaginal ring — The estrogen vaginal ring (Estring®) is inserted into the vagina and releases estrogen in a controlled fashion over three months. Very small amounts are released into the vagina. The estrogen appears to act only on the tissues of the vagina with little to no estrogen absorbed into the bloodstream. Studies show that women using the ring experience very few side effects. Some women prefer the convenience of the ring over vaginal creams. The ring is changed once every three months by the woman or her healthcare provider. These low dose vaginal rings should not be confused with a high dose ring (Femring®) which has a higher dose of estrogen and is absorbed into the bloodstream to relieve hot flashes.
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)
The Mayo Clinic
(www.mayoclinic.com)
U.S. Department of Health and Human Services
Agency for Healthcare Research and Quality
(www.ahrq.gov)
American Academy of Family Physicians
(www.familydoctor.org)
[1-10]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Loprinzi, CL, Levitt, R, Barton, D, et al. Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol 2006; 24:1409.
2. Loprinzi, CL, Kugler, JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000; 356:2059.
3. Stearns, V, Beebe, KL, Iyengar, M, Dube, E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003; 289:2827.
4. Loprinzi, CL, Sloan, JA, Perez, EA, et al. Phase III Evaluation of Fluoxetine for Treatment of Hot Flashes. J Clin Oncol 2002; 20:1578.
5. Stearns, V, Slack, R, Greep, N, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 2005; 23:6919.
6. Hsia, J, Langer, RD, Manson, JE, et al. Conjugated Equine Estrogens and Coronary Heart Disease: The Women's Health Initiative. Arch Intern Med 2006; 166:357.
7. Grodstein, F, Manson, JE, Stampfer, MJ. Hormone Therapy and Coronary Heart Disease: The Role of Time since Menopause and Age at Hormone Initiation. J Womens Health (Larchmt) 2006; 15:35.
8. Pinkerton, JV, Santen, R. Alternatives to the use of estrogen in postmenopausal women. Endocr Rev 1999; 20:308.
9. 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.
10. 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.
Hormone replacement therapy (HRT) is the term used for estrogen or for estrogen plus progestin treatment after menopause. Progestins are drugs that act like the female hormone progesterone, and they are added to the estrogen to prevent uterine cancer (which can occur if estrogen alone is given to women with a uterus). HRT is an effective option for treating the symptoms of menopause, and it helps prevent osteoporosis.
STUDIES OF HORMONE REPLACEMENT — Previously, scientists thought HRT would reduce the risk of heart disease in postmenopausal women. However, data from large studies such as the Women's Health Initiative (WHI) and HERS trials have shown that combined estrogen-progestin therapy does not reduce the risk of heart disease. In fact, estrogen plus progesterone might increase risk slightly [1,2].
More recent studies, however, suggest that HRT might protect against heart disease in younger postmenopausal women (ie, those 50 to 59 years of age). In the WHI trial of estrogen alone, there was no increased risk of heart disease but the risk of stroke was increased.
The WHI also reported an increased risk of breast cancer with combined estrogen-progestin (similar to that seen in previous studies), and an increase in stroke and blood clots (in the leg and lung). On the other hand, a decrease in the risk of colon cancer and fractures (due to osteoporosis) was also seen. However, the investigators concluded that the risks of HRT may outweigh its benefits in many women.
The results of the WHI trial of unopposed estrogen were quite different. While an increase in strokes and blood clots was seen, there was no increase in breast cancer risk. (See "Patient information: Postmenopausal hormone therapy").
Data from the WHI and the HERS trials have led to changes in our recommendations for estrogen therapy. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer, while unopposed estrogen appears to increase stroke risk; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. As a result, the primary indication for estrogen therapy at present is for control of menopausal symptoms. For long-term prevention of heart disease and osteoporosis, most women need to consider lifestyle interventions and medications other than estrogen.
A number of alternatives are now available to control menopausal symptoms. This is particularly important for women who have had breast cancer, because hormone therapy appears to increase the risk of recurrence. (See "Patient information: Postmenopausal hormone therapy").
PREVENTING AND TREATING OSTEOPOROSIS — When estrogen levels fall, bone density (strength) starts to decline, and, over time, a woman can develop osteoporosis and even fractures. Your doctor may recommend bone mineral density tests (ie, DEXA scan) to monitor for early bone loss. Several alternatives to HRT can help keep bones strong and even partially reverse osteoporosis, but effective treatment for established osteoporosis usually requires the combination of changes in diet, lifestyle, and medication. (See "Patient information: Osteoporosis causes, diagnosis, and screening" and see "Patient information: Osteoporosis prevention and treatment").
Calcium — Calcium is an essential component of bones, and calcium from foods we eat can help strengthen bones. However, calcium alone cannot always prevent osteoporosis. All postmenopausal women need 1500 mg of calcium each day. Most women will need to eat a well-balanced diet and take a daily supplement that contains 1000 mg of calcium, usually in the form of calcium carbonate, calcium citrate, or an equivalent calcium compound. A list of calcium-rich foods and guidelines for choosing calcium supplements (show figure 1). (See "Patient information: Calcium for bone health").
Vitamin D — Vitamin D helps the body absorb calcium and incorporate calcium into bone. It is therefore also important for bone strength. Many older adults, particularly those over 70 years, have vitamin D deficiencies. Postmenopausal women under the age of 70 years should get at least 400 IU of vitamin D each day in their diet or with a vitamin supplement. Women over 70 years should take 800 IU of vitamin D. Some calcium supplements include vitamin D; patients should read the label to know the amount included.
Exercise — Bones remain stronger when they are used in day-to-day activities, and inactivity increases the rate of postmenopausal bone loss. At least 30 minutes of weight-bearing exercise three times a week can reduce this loss. Weight-bearing exercise includes activities such as walking, aerobics, or tennis, but does not include bicycling or swimming.
Medications — Several medications, such as alendronate, risedronate, ibandronate, zoledronic acid, tamoxifen, and raloxifene can help prevent or even reverse osteoporosis by boosting bone density. These medications can even benefit women who have already suffered fractures. Women taking these medications should continue to take calcium and to follow other measures that promote bone strength. A new drug, human parathyroid hormone (Forteo), given by daily injection under the skin, is now available for the treatment of severe osteoporosis.
Alendronate, risedronate, and ibandronate — Alendronate (Fosamax®), risedronate (Actonel®), and ibandronate (Boniva®) are prescribed for the prevention and treatment of osteoporosis in postmenopausal women. They are able to prevent and reverse bone loss as effectively as estrogen. Women need to take these medications with water 30 minutes before eating in the morning and must sit upright or stand for this time period, to prevent pill-associated irritation of the esophagus (the part of the digestive tract between the mouth and stomach). Women who already have esophageal problems such as heartburn or esophagitis should not take these medications. Preparations are now available that allow patients to take alendronate once weekly and ibandronate once monthly.
Tamoxifen and raloxifene — Tamoxifen (Nolvadex®) is usually prescribed for women with breast cancer. Tamoxifen opposes the action of estrogen in breast tissue, but actually has an estrogen-like effect on bone in post-menopausal women. As a result, tamoxifen increases bone mineral density and decreases the number of bone fractures in postmenopausal women. The most bothersome side effect of tamoxifen is hot flashes. Tamoxifen is usually taken once daily, but is not prescribed for more than five years in women who have had breast cancer. Tamoxifen is also used for prevention of breast cancer in women at high risk. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
Raloxifene (Evista®) is similar to tamoxifen in that it has an anti-estrogen effect on breast tissue and an estrogen-like effect on bone. In contrast to tamoxifen, it does not cause uterine cancer. It is used for the prevention and treatment of osteoporosis, and has been tested for breast cancer prevention in women who are at high risk. Hot flashes are a side effect in some women who take raloxifene.
PREVENTING CARDIOVASCULAR DISEASE — The fall of estrogen concentrations after menopause is associated with an increased risk of developing and dying from cardiovascular disease. Replacing estrogen does not lower this risk in women over 60 years of age. Alternatives to HRT can effectively reduce some of the risk factors associated with cardiovascular disease, such as high cholesterol levels.
Smoking cessation — Quitting smoking is probably the most important change a woman can make to decrease her risk of developing heart disease. Be sure to ask your doctor about methods for successfully quitting. (See "Patient information: Smoking cessation").
Dietary modification — Before prescribing any medication, your doctor may recommend a trial of a low-fat diet to bring cholesterol levels under control. If this approach is successful, medication may not be necessary. (See "Patient information: Diet and health").
Cholesterol-regulating medication — In postmenopausal women with high serum cholesterol levels, medications such as statins (ie, simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin) lower levels of total and low-density-lipoprotein (LDL) cholesterol ("bad" cholesterol). These medications also decrease a woman's risk of heart disease. HRT does not prevent heart disease while the statin drugs have been shown to have this effect. (See "Patient information: High cholesterol and lipids (hyperlipidemia)").
CONTROLLING HOT FLASHES — New alternatives for the treatment of hot flashes have been tested and shown to be effective. None work nearly as well as estrogen, but relief from these agents is about 70 percent as effective as estrogen. No treatment may be necessary since hot flashes typically subside after one to two years, even without treatment, and may not be particularly severe. Some of the treatments that can give partial relief of hot flashes include:
Antidepressants — Venlafaxine (Effexor®), and paroxetine (Paxil®) have been shown to relieve hot flashes. This type of medication is usually used to treat depression, but more recent studies show them to be effective for hot flashes. Venlafaxine has been more extensively studied than the others. Fluoxetine (Prozac®) is also effective. These medications can be tried first in women who cannot take estrogen who suffer with hot flashes . However, side effects can occur with these medications as well. Women taking tamoxifen should be cautioned that paroxetine and sertraline (Zoloft®) interfere with the action of tamoxifen.
Clonidine — Clonidine, a blood pressure lowering drug, helps relieve hot flashes in some women. Clonidine is administered by transdermal skin patch (Duraclon®), oral medication (Catapres®), or a combination of both. Clonidine seems to work well in some patients and to be completely ineffective in others. Only a trial of medication can identify those women who receive benefit. Side effects can range from dry mouth and constipation to dizziness and sedation.
Gabapentin — Gabapentin (Neurontin®) is a drug that is primarily used for the treatment of seizures. Although it has not been as well studied as the SSRIs, it appears to be moderately effective for hot flushes and is well tolerated. Because its main side effect is drowsiness, gabapentin is most effective in reducing early morning awakening which can accompany hot flashes.
Megestrol acetate — Megestrol acetate (Megace®) is a hormone that is sometimes used for women who have had breast cancer. It is nearly as effective as estrogen, but can only be given short-term (for several months). Prolonged use of megestrol acetate can lead to weight gain and serious effects can occur if the medication is stopped abruptly. For this reason, the SSRI class of drugs is used before trying megestrol acetate. Recent studies also demonstrate benefit of an injectable progestin hormone, medroxyprogesterone acetate (Depo-Provera®). Depo-Provera® can be used long-term, though can also have side effects, including weight gain and loss of bone density.
Plant-derived estrogens — Plant-derived estrogens, also called phytoestrogens, sometimes help relieve hot flashes somewhat. Dietary sources of phystoestrogens include soy products. Other phytoestrogens such as ginseng, dong quai, and black cohosh can be purchased at health-food stores. However, these supplements might increase breast cancer risk because they act like estrogen in some tissues of the body. The efficacy of these supplements for hot flashes has not been rigorously proven. The same precautions should be used for these compounds as with HRT in breast cancer survivors.
TREATING VAGINAL DRYNESS — When estrogen production falls, the lining of the vagina thins, leading to vaginal dryness, and sometimes painful sexual intercourse. Several alternatives to estrogen can help control these symptoms. (See "Patient information: Sexual problems in women").
Moisturizers and lubricants — Regular use of vaginal moisturizing agents, such as Replens® or KY Long Lasting®, can help relieve vaginal dryness and irritation. These agents must be used regularly and at times other than before intercourse since they work by moisturizing the vaginal tissues, but can be irritating on direct contact.
Lubricants can prevent pain during sexual intercourse and are used immediately before intercourse. Water-soluble lubricants, such as Astroglide®, are more effective for intercourse than lubricants such as K-Y jelly. Products such as petroleum jelly or hand and body lotions should not be used to relieve vaginal dryness since they can be irritating to the vaginal tissues.
Vaginal estrogens — Estrogen creams, such as Premarin® or Estrace®, can be applied directly to the vagina. When applied in a very low dose, they improve the health of the vaginal tissues without substantially increasing levels of estrogen in the bloodstream. Vaginal estrogen creams are given every day for two to three weeks, and then only once or twice weekly to maintain the effects. They are more effective than moisturizers and lubricants for relieving vaginal symptoms. The lowest dose which is effective should be used. Vaginal estrogen tablets (Vagifem®) and very low-dose vaginal estrogen rings (Estring®) are similarly effective and may be less messy and more convenient than estrogen creams.
Vaginal ring — The estrogen vaginal ring (Estring®) is inserted into the vagina and releases estrogen in a controlled fashion over three months. Very small amounts are released into the vagina. The estrogen appears to act only on the tissues of the vagina with little to no estrogen absorbed into the bloodstream. Studies show that women using the ring experience very few side effects. Some women prefer the convenience of the ring over vaginal creams. The ring is changed once every three months by the woman or her healthcare provider. These low dose vaginal rings should not be confused with a high dose ring (Femring®) which has a higher dose of estrogen and is absorbed into the bloodstream to relieve hot flashes.
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)
The Mayo Clinic
(www.mayoclinic.com)
U.S. Department of Health and Human Services
Agency for Healthcare Research and Quality
(www.ahrq.gov)
American Academy of Family Physicians
(www.familydoctor.org)
[1-10]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Loprinzi, CL, Levitt, R, Barton, D, et al. Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol 2006; 24:1409.
2. Loprinzi, CL, Kugler, JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000; 356:2059.
3. Stearns, V, Beebe, KL, Iyengar, M, Dube, E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003; 289:2827.
4. Loprinzi, CL, Sloan, JA, Perez, EA, et al. Phase III Evaluation of Fluoxetine for Treatment of Hot Flashes. J Clin Oncol 2002; 20:1578.
5. Stearns, V, Slack, R, Greep, N, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 2005; 23:6919.
6. Hsia, J, Langer, RD, Manson, JE, et al. Conjugated Equine Estrogens and Coronary Heart Disease: The Women's Health Initiative. Arch Intern Med 2006; 166:357.
7. Grodstein, F, Manson, JE, Stampfer, MJ. Hormone Therapy and Coronary Heart Disease: The Role of Time since Menopause and Age at Hormone Initiation. J Womens Health (Larchmt) 2006; 15:35.
8. Pinkerton, JV, Santen, R. Alternatives to the use of estrogen in postmenopausal women. Endocr Rev 1999; 20:308.
9. 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.
10. 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.
Alternatives to postmenopausal hormone therapy
INTRODUCTION — During a woman's reproductive years, the body produces a variety of hormones, including estrogen. Estrogen is important for normal menstrual periods and fertility, and it promotes bone strength. Estrogen levels fall at the time of menopause, causing well-known symptoms such as hot flashes. This fall in estrogen increases a woman's risk of osteoporosis and heart disease.
Hormone replacement therapy (HRT) is the term used for estrogen or for estrogen plus progestin treatment after menopause. Progestins are drugs that act like the female hormone progesterone, and they are added to the estrogen to prevent uterine cancer (which can occur if estrogen alone is given to women with a uterus). HRT is an effective option for treating the symptoms of menopause, and it helps prevent osteoporosis.
STUDIES OF HORMONE REPLACEMENT — Previously, scientists thought HRT would reduce the risk of heart disease in postmenopausal women. However, data from large studies such as the Women's Health Initiative (WHI) and HERS trials have shown that combined estrogen-progestin therapy does not reduce the risk of heart disease. In fact, estrogen plus progesterone might increase risk slightly [1,2].
More recent studies, however, suggest that HRT might protect against heart disease in younger postmenopausal women (ie, those 50 to 59 years of age). In the WHI trial of estrogen alone, there was no increased risk of heart disease but the risk of stroke was increased.
The WHI also reported an increased risk of breast cancer with combined estrogen-progestin (similar to that seen in previous studies), and an increase in stroke and blood clots (in the leg and lung). On the other hand, a decrease in the risk of colon cancer and fractures (due to osteoporosis) was also seen. However, the investigators concluded that the risks of HRT may outweigh its benefits in many women.
The results of the WHI trial of unopposed estrogen were quite different. While an increase in strokes and blood clots was seen, there was no increase in breast cancer risk. (See "Patient information: Postmenopausal hormone therapy").
Data from the WHI and the HERS trials have led to changes in our recommendations for estrogen therapy. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer, while unopposed estrogen appears to increase stroke risk; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. As a result, the primary indication for estrogen therapy at present is for control of menopausal symptoms. For long-term prevention of heart disease and osteoporosis, most women need to consider lifestyle interventions and medications other than estrogen.
A number of alternatives are now available to control menopausal symptoms. This is particularly important for women who have had breast cancer, because hormone therapy appears to increase the risk of recurrence. (See "Patient information: Postmenopausal hormone therapy").
PREVENTING AND TREATING OSTEOPOROSIS — When estrogen levels fall, bone density (strength) starts to decline, and, over time, a woman can develop osteoporosis and even fractures. Your doctor may recommend bone mineral density tests (ie, DEXA scan) to monitor for early bone loss. Several alternatives to HRT can help keep bones strong and even partially reverse osteoporosis, but effective treatment for established osteoporosis usually requires the combination of changes in diet, lifestyle, and medication. (See "Patient information: Osteoporosis causes, diagnosis, and screening" and see "Patient information: Osteoporosis prevention and treatment").
Calcium — Calcium is an essential component of bones, and calcium from foods we eat can help strengthen bones. However, calcium alone cannot always prevent osteoporosis. All postmenopausal women need 1500 mg of calcium each day. Most women will need to eat a well-balanced diet and take a daily supplement that contains 1000 mg of calcium, usually in the form of calcium carbonate, calcium citrate, or an equivalent calcium compound. A list of calcium-rich foods and guidelines for choosing calcium supplements (show figure 1). (See "Patient information: Calcium for bone health").
Vitamin D — Vitamin D helps the body absorb calcium and incorporate calcium into bone. It is therefore also important for bone strength. Many older adults, particularly those over 70 years, have vitamin D deficiencies. Postmenopausal women under the age of 70 years should get at least 400 IU of vitamin D each day in their diet or with a vitamin supplement. Women over 70 years should take 800 IU of vitamin D. Some calcium supplements include vitamin D; patients should read the label to know the amount included.
Exercise — Bones remain stronger when they are used in day-to-day activities, and inactivity increases the rate of postmenopausal bone loss. At least 30 minutes of weight-bearing exercise three times a week can reduce this loss. Weight-bearing exercise includes activities such as walking, aerobics, or tennis, but does not include bicycling or swimming.
Medications — Several medications, such as alendronate, risedronate, ibandronate, zoledronic acid, tamoxifen, and raloxifene can help prevent or even reverse osteoporosis by boosting bone density. These medications can even benefit women who have already suffered fractures. Women taking these medications should continue to take calcium and to follow other measures that promote bone strength. A new drug, human parathyroid hormone (Forteo), given by daily injection under the skin, is now available for the treatment of severe osteoporosis.
Alendronate, risedronate, and ibandronate — Alendronate (Fosamax®), risedronate (Actonel®), and ibandronate (Boniva®) are prescribed for the prevention and treatment of osteoporosis in postmenopausal women. They are able to prevent and reverse bone loss as effectively as estrogen. Women need to take these medications with water 30 minutes before eating in the morning and must sit upright or stand for this time period, to prevent pill-associated irritation of the esophagus (the part of the digestive tract between the mouth and stomach). Women who already have esophageal problems such as heartburn or esophagitis should not take these medications. Preparations are now available that allow patients to take alendronate once weekly and ibandronate once monthly.
Tamoxifen and raloxifene — Tamoxifen (Nolvadex®) is usually prescribed for women with breast cancer. Tamoxifen opposes the action of estrogen in breast tissue, but actually has an estrogen-like effect on bone in post-menopausal women. As a result, tamoxifen increases bone mineral density and decreases the number of bone fractures in postmenopausal women. The most bothersome side effect of tamoxifen is hot flashes. Tamoxifen is usually taken once daily, but is not prescribed for more than five years in women who have had breast cancer. Tamoxifen is also used for prevention of breast cancer in women at high risk. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
Raloxifene (Evista®) is similar to tamoxifen in that it has an anti-estrogen effect on breast tissue and an estrogen-like effect on bone. In contrast to tamoxifen, it does not cause uterine cancer. It is used for the prevention and treatment of osteoporosis, and has been tested for breast cancer prevention in women who are at high risk. Hot flashes are a side effect in some women who take raloxifene.
PREVENTING CARDIOVASCULAR DISEASE — The fall of estrogen concentrations after menopause is associated with an increased risk of developing and dying from cardiovascular disease. Replacing estrogen does not lower this risk in women over 60 years of age. Alternatives to HRT can effectively reduce some of the risk factors associated with cardiovascular disease, such as high cholesterol levels.
Smoking cessation — Quitting smoking is probably the most important change a woman can make to decrease her risk of developing heart disease. Be sure to ask your doctor about methods for successfully quitting. (See "Patient information: Smoking cessation").
Dietary modification — Before prescribing any medication, your doctor may recommend a trial of a low-fat diet to bring cholesterol levels under control. If this approach is successful, medication may not be necessary. (See "Patient information: Diet and health").
Cholesterol-regulating medication — In postmenopausal women with high serum cholesterol levels, medications such as statins (ie, simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin) lower levels of total and low-density-lipoprotein (LDL) cholesterol ("bad" cholesterol). These medications also decrease a woman's risk of heart disease. HRT does not prevent heart disease while the statin drugs have been shown to have this effect. (See "Patient information: High cholesterol and lipids (hyperlipidemia)").
CONTROLLING HOT FLASHES — New alternatives for the treatment of hot flashes have been tested and shown to be effective. None work nearly as well as estrogen, but relief from these agents is about 70 percent as effective as estrogen. No treatment may be necessary since hot flashes typically subside after one to two years, even without treatment, and may not be particularly severe. Some of the treatments that can give partial relief of hot flashes include:
Antidepressants — Venlafaxine (Effexor®), and paroxetine (Paxil®) have been shown to relieve hot flashes. This type of medication is usually used to treat depression, but more recent studies show them to be effective for hot flashes. Venlafaxine has been more extensively studied than the others. Fluoxetine (Prozac®) is also effective. These medications can be tried first in women who cannot take estrogen who suffer with hot flashes . However, side effects can occur with these medications as well. Women taking tamoxifen should be cautioned that paroxetine and sertraline (Zoloft®) interfere with the action of tamoxifen.
Clonidine — Clonidine, a blood pressure lowering drug, helps relieve hot flashes in some women. Clonidine is administered by transdermal skin patch (Duraclon®), oral medication (Catapres®), or a combination of both. Clonidine seems to work well in some patients and to be completely ineffective in others. Only a trial of medication can identify those women who receive benefit. Side effects can range from dry mouth and constipation to dizziness and sedation.
Gabapentin — Gabapentin (Neurontin®) is a drug that is primarily used for the treatment of seizures. Although it has not been as well studied as the SSRIs, it appears to be moderately effective for hot flushes and is well tolerated. Because its main side effect is drowsiness, gabapentin is most effective in reducing early morning awakening which can accompany hot flashes.
Megestrol acetate — Megestrol acetate (Megace®) is a hormone that is sometimes used for women who have had breast cancer. It is nearly as effective as estrogen, but can only be given short-term (for several months). Prolonged use of megestrol acetate can lead to weight gain and serious effects can occur if the medication is stopped abruptly. For this reason, the SSRI class of drugs is used before trying megestrol acetate. Recent studies also demonstrate benefit of an injectable progestin hormone, medroxyprogesterone acetate (Depo-Provera®). Depo-Provera® can be used long-term, though can also have side effects, including weight gain and loss of bone density.
Plant-derived estrogens — Plant-derived estrogens, also called phytoestrogens, sometimes help relieve hot flashes somewhat. Dietary sources of phystoestrogens include soy products. Other phytoestrogens such as ginseng, dong quai, and black cohosh can be purchased at health-food stores. However, these supplements might increase breast cancer risk because they act like estrogen in some tissues of the body. The efficacy of these supplements for hot flashes has not been rigorously proven. The same precautions should be used for these compounds as with HRT in breast cancer survivors.
TREATING VAGINAL DRYNESS — When estrogen production falls, the lining of the vagina thins, leading to vaginal dryness, and sometimes painful sexual intercourse. Several alternatives to estrogen can help control these symptoms. (See "Patient information: Sexual problems in women").
Moisturizers and lubricants — Regular use of vaginal moisturizing agents, such as Replens® or KY Long Lasting®, can help relieve vaginal dryness and irritation. These agents must be used regularly and at times other than before intercourse since they work by moisturizing the vaginal tissues, but can be irritating on direct contact.
Lubricants can prevent pain during sexual intercourse and are used immediately before intercourse. Water-soluble lubricants, such as Astroglide®, are more effective for intercourse than lubricants such as K-Y jelly. Products such as petroleum jelly or hand and body lotions should not be used to relieve vaginal dryness since they can be irritating to the vaginal tissues.
Vaginal estrogens — Estrogen creams, such as Premarin® or Estrace®, can be applied directly to the vagina. When applied in a very low dose, they improve the health of the vaginal tissues without substantially increasing levels of estrogen in the bloodstream. Vaginal estrogen creams are given every day for two to three weeks, and then only once or twice weekly to maintain the effects. They are more effective than moisturizers and lubricants for relieving vaginal symptoms. The lowest dose which is effective should be used. Vaginal estrogen tablets (Vagifem®) and very low-dose vaginal estrogen rings (Estring®) are similarly effective and may be less messy and more convenient than estrogen creams.
Vaginal ring — The estrogen vaginal ring (Estring®) is inserted into the vagina and releases estrogen in a controlled fashion over three months. Very small amounts are released into the vagina. The estrogen appears to act only on the tissues of the vagina with little to no estrogen absorbed into the bloodstream. Studies show that women using the ring experience very few side effects. Some women prefer the convenience of the ring over vaginal creams. The ring is changed once every three months by the woman or her healthcare provider. These low dose vaginal rings should not be confused with a high dose ring (Femring®) which has a higher dose of estrogen and is absorbed into the bloodstream to relieve hot flashes.
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)
The Mayo Clinic
(www.mayoclinic.com)
U.S. Department of Health and Human Services
Agency for Healthcare Research and Quality
(www.ahrq.gov)
American Academy of Family Physicians
(www.familydoctor.org)
[1-10]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Loprinzi, CL, Levitt, R, Barton, D, et al. Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol 2006; 24:1409.
2. Loprinzi, CL, Kugler, JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000; 356:2059.
3. Stearns, V, Beebe, KL, Iyengar, M, Dube, E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003; 289:2827.
4. Loprinzi, CL, Sloan, JA, Perez, EA, et al. Phase III Evaluation of Fluoxetine for Treatment of Hot Flashes. J Clin Oncol 2002; 20:1578.
5. Stearns, V, Slack, R, Greep, N, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 2005; 23:6919.
6. Hsia, J, Langer, RD, Manson, JE, et al. Conjugated Equine Estrogens and Coronary Heart Disease: The Women's Health Initiative. Arch Intern Med 2006; 166:357.
7. Grodstein, F, Manson, JE, Stampfer, MJ. Hormone Therapy and Coronary Heart Disease: The Role of Time since Menopause and Age at Hormone Initiation. J Womens Health (Larchmt) 2006; 15:35.
8. Pinkerton, JV, Santen, R. Alternatives to the use of estrogen in postmenopausal women. Endocr Rev 1999; 20:308.
9. 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.
10. 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.
Hormone replacement therapy (HRT) is the term used for estrogen or for estrogen plus progestin treatment after menopause. Progestins are drugs that act like the female hormone progesterone, and they are added to the estrogen to prevent uterine cancer (which can occur if estrogen alone is given to women with a uterus). HRT is an effective option for treating the symptoms of menopause, and it helps prevent osteoporosis.
STUDIES OF HORMONE REPLACEMENT — Previously, scientists thought HRT would reduce the risk of heart disease in postmenopausal women. However, data from large studies such as the Women's Health Initiative (WHI) and HERS trials have shown that combined estrogen-progestin therapy does not reduce the risk of heart disease. In fact, estrogen plus progesterone might increase risk slightly [1,2].
More recent studies, however, suggest that HRT might protect against heart disease in younger postmenopausal women (ie, those 50 to 59 years of age). In the WHI trial of estrogen alone, there was no increased risk of heart disease but the risk of stroke was increased.
The WHI also reported an increased risk of breast cancer with combined estrogen-progestin (similar to that seen in previous studies), and an increase in stroke and blood clots (in the leg and lung). On the other hand, a decrease in the risk of colon cancer and fractures (due to osteoporosis) was also seen. However, the investigators concluded that the risks of HRT may outweigh its benefits in many women.
The results of the WHI trial of unopposed estrogen were quite different. While an increase in strokes and blood clots was seen, there was no increase in breast cancer risk. (See "Patient information: Postmenopausal hormone therapy").
Data from the WHI and the HERS trials have led to changes in our recommendations for estrogen therapy. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer, while unopposed estrogen appears to increase stroke risk; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. As a result, the primary indication for estrogen therapy at present is for control of menopausal symptoms. For long-term prevention of heart disease and osteoporosis, most women need to consider lifestyle interventions and medications other than estrogen.
A number of alternatives are now available to control menopausal symptoms. This is particularly important for women who have had breast cancer, because hormone therapy appears to increase the risk of recurrence. (See "Patient information: Postmenopausal hormone therapy").
PREVENTING AND TREATING OSTEOPOROSIS — When estrogen levels fall, bone density (strength) starts to decline, and, over time, a woman can develop osteoporosis and even fractures. Your doctor may recommend bone mineral density tests (ie, DEXA scan) to monitor for early bone loss. Several alternatives to HRT can help keep bones strong and even partially reverse osteoporosis, but effective treatment for established osteoporosis usually requires the combination of changes in diet, lifestyle, and medication. (See "Patient information: Osteoporosis causes, diagnosis, and screening" and see "Patient information: Osteoporosis prevention and treatment").
Calcium — Calcium is an essential component of bones, and calcium from foods we eat can help strengthen bones. However, calcium alone cannot always prevent osteoporosis. All postmenopausal women need 1500 mg of calcium each day. Most women will need to eat a well-balanced diet and take a daily supplement that contains 1000 mg of calcium, usually in the form of calcium carbonate, calcium citrate, or an equivalent calcium compound. A list of calcium-rich foods and guidelines for choosing calcium supplements (show figure 1). (See "Patient information: Calcium for bone health").
Vitamin D — Vitamin D helps the body absorb calcium and incorporate calcium into bone. It is therefore also important for bone strength. Many older adults, particularly those over 70 years, have vitamin D deficiencies. Postmenopausal women under the age of 70 years should get at least 400 IU of vitamin D each day in their diet or with a vitamin supplement. Women over 70 years should take 800 IU of vitamin D. Some calcium supplements include vitamin D; patients should read the label to know the amount included.
Exercise — Bones remain stronger when they are used in day-to-day activities, and inactivity increases the rate of postmenopausal bone loss. At least 30 minutes of weight-bearing exercise three times a week can reduce this loss. Weight-bearing exercise includes activities such as walking, aerobics, or tennis, but does not include bicycling or swimming.
Medications — Several medications, such as alendronate, risedronate, ibandronate, zoledronic acid, tamoxifen, and raloxifene can help prevent or even reverse osteoporosis by boosting bone density. These medications can even benefit women who have already suffered fractures. Women taking these medications should continue to take calcium and to follow other measures that promote bone strength. A new drug, human parathyroid hormone (Forteo), given by daily injection under the skin, is now available for the treatment of severe osteoporosis.
Alendronate, risedronate, and ibandronate — Alendronate (Fosamax®), risedronate (Actonel®), and ibandronate (Boniva®) are prescribed for the prevention and treatment of osteoporosis in postmenopausal women. They are able to prevent and reverse bone loss as effectively as estrogen. Women need to take these medications with water 30 minutes before eating in the morning and must sit upright or stand for this time period, to prevent pill-associated irritation of the esophagus (the part of the digestive tract between the mouth and stomach). Women who already have esophageal problems such as heartburn or esophagitis should not take these medications. Preparations are now available that allow patients to take alendronate once weekly and ibandronate once monthly.
Tamoxifen and raloxifene — Tamoxifen (Nolvadex®) is usually prescribed for women with breast cancer. Tamoxifen opposes the action of estrogen in breast tissue, but actually has an estrogen-like effect on bone in post-menopausal women. As a result, tamoxifen increases bone mineral density and decreases the number of bone fractures in postmenopausal women. The most bothersome side effect of tamoxifen is hot flashes. Tamoxifen is usually taken once daily, but is not prescribed for more than five years in women who have had breast cancer. Tamoxifen is also used for prevention of breast cancer in women at high risk. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
Raloxifene (Evista®) is similar to tamoxifen in that it has an anti-estrogen effect on breast tissue and an estrogen-like effect on bone. In contrast to tamoxifen, it does not cause uterine cancer. It is used for the prevention and treatment of osteoporosis, and has been tested for breast cancer prevention in women who are at high risk. Hot flashes are a side effect in some women who take raloxifene.
PREVENTING CARDIOVASCULAR DISEASE — The fall of estrogen concentrations after menopause is associated with an increased risk of developing and dying from cardiovascular disease. Replacing estrogen does not lower this risk in women over 60 years of age. Alternatives to HRT can effectively reduce some of the risk factors associated with cardiovascular disease, such as high cholesterol levels.
Smoking cessation — Quitting smoking is probably the most important change a woman can make to decrease her risk of developing heart disease. Be sure to ask your doctor about methods for successfully quitting. (See "Patient information: Smoking cessation").
Dietary modification — Before prescribing any medication, your doctor may recommend a trial of a low-fat diet to bring cholesterol levels under control. If this approach is successful, medication may not be necessary. (See "Patient information: Diet and health").
Cholesterol-regulating medication — In postmenopausal women with high serum cholesterol levels, medications such as statins (ie, simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin) lower levels of total and low-density-lipoprotein (LDL) cholesterol ("bad" cholesterol). These medications also decrease a woman's risk of heart disease. HRT does not prevent heart disease while the statin drugs have been shown to have this effect. (See "Patient information: High cholesterol and lipids (hyperlipidemia)").
CONTROLLING HOT FLASHES — New alternatives for the treatment of hot flashes have been tested and shown to be effective. None work nearly as well as estrogen, but relief from these agents is about 70 percent as effective as estrogen. No treatment may be necessary since hot flashes typically subside after one to two years, even without treatment, and may not be particularly severe. Some of the treatments that can give partial relief of hot flashes include:
Antidepressants — Venlafaxine (Effexor®), and paroxetine (Paxil®) have been shown to relieve hot flashes. This type of medication is usually used to treat depression, but more recent studies show them to be effective for hot flashes. Venlafaxine has been more extensively studied than the others. Fluoxetine (Prozac®) is also effective. These medications can be tried first in women who cannot take estrogen who suffer with hot flashes . However, side effects can occur with these medications as well. Women taking tamoxifen should be cautioned that paroxetine and sertraline (Zoloft®) interfere with the action of tamoxifen.
Clonidine — Clonidine, a blood pressure lowering drug, helps relieve hot flashes in some women. Clonidine is administered by transdermal skin patch (Duraclon®), oral medication (Catapres®), or a combination of both. Clonidine seems to work well in some patients and to be completely ineffective in others. Only a trial of medication can identify those women who receive benefit. Side effects can range from dry mouth and constipation to dizziness and sedation.
Gabapentin — Gabapentin (Neurontin®) is a drug that is primarily used for the treatment of seizures. Although it has not been as well studied as the SSRIs, it appears to be moderately effective for hot flushes and is well tolerated. Because its main side effect is drowsiness, gabapentin is most effective in reducing early morning awakening which can accompany hot flashes.
Megestrol acetate — Megestrol acetate (Megace®) is a hormone that is sometimes used for women who have had breast cancer. It is nearly as effective as estrogen, but can only be given short-term (for several months). Prolonged use of megestrol acetate can lead to weight gain and serious effects can occur if the medication is stopped abruptly. For this reason, the SSRI class of drugs is used before trying megestrol acetate. Recent studies also demonstrate benefit of an injectable progestin hormone, medroxyprogesterone acetate (Depo-Provera®). Depo-Provera® can be used long-term, though can also have side effects, including weight gain and loss of bone density.
Plant-derived estrogens — Plant-derived estrogens, also called phytoestrogens, sometimes help relieve hot flashes somewhat. Dietary sources of phystoestrogens include soy products. Other phytoestrogens such as ginseng, dong quai, and black cohosh can be purchased at health-food stores. However, these supplements might increase breast cancer risk because they act like estrogen in some tissues of the body. The efficacy of these supplements for hot flashes has not been rigorously proven. The same precautions should be used for these compounds as with HRT in breast cancer survivors.
TREATING VAGINAL DRYNESS — When estrogen production falls, the lining of the vagina thins, leading to vaginal dryness, and sometimes painful sexual intercourse. Several alternatives to estrogen can help control these symptoms. (See "Patient information: Sexual problems in women").
Moisturizers and lubricants — Regular use of vaginal moisturizing agents, such as Replens® or KY Long Lasting®, can help relieve vaginal dryness and irritation. These agents must be used regularly and at times other than before intercourse since they work by moisturizing the vaginal tissues, but can be irritating on direct contact.
Lubricants can prevent pain during sexual intercourse and are used immediately before intercourse. Water-soluble lubricants, such as Astroglide®, are more effective for intercourse than lubricants such as K-Y jelly. Products such as petroleum jelly or hand and body lotions should not be used to relieve vaginal dryness since they can be irritating to the vaginal tissues.
Vaginal estrogens — Estrogen creams, such as Premarin® or Estrace®, can be applied directly to the vagina. When applied in a very low dose, they improve the health of the vaginal tissues without substantially increasing levels of estrogen in the bloodstream. Vaginal estrogen creams are given every day for two to three weeks, and then only once or twice weekly to maintain the effects. They are more effective than moisturizers and lubricants for relieving vaginal symptoms. The lowest dose which is effective should be used. Vaginal estrogen tablets (Vagifem®) and very low-dose vaginal estrogen rings (Estring®) are similarly effective and may be less messy and more convenient than estrogen creams.
Vaginal ring — The estrogen vaginal ring (Estring®) is inserted into the vagina and releases estrogen in a controlled fashion over three months. Very small amounts are released into the vagina. The estrogen appears to act only on the tissues of the vagina with little to no estrogen absorbed into the bloodstream. Studies show that women using the ring experience very few side effects. Some women prefer the convenience of the ring over vaginal creams. The ring is changed once every three months by the woman or her healthcare provider. These low dose vaginal rings should not be confused with a high dose ring (Femring®) which has a higher dose of estrogen and is absorbed into the bloodstream to relieve hot flashes.
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)
The Mayo Clinic
(www.mayoclinic.com)
U.S. Department of Health and Human Services
Agency for Healthcare Research and Quality
(www.ahrq.gov)
American Academy of Family Physicians
(www.familydoctor.org)
[1-10]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Loprinzi, CL, Levitt, R, Barton, D, et al. Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol 2006; 24:1409.
2. Loprinzi, CL, Kugler, JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000; 356:2059.
3. Stearns, V, Beebe, KL, Iyengar, M, Dube, E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003; 289:2827.
4. Loprinzi, CL, Sloan, JA, Perez, EA, et al. Phase III Evaluation of Fluoxetine for Treatment of Hot Flashes. J Clin Oncol 2002; 20:1578.
5. Stearns, V, Slack, R, Greep, N, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 2005; 23:6919.
6. Hsia, J, Langer, RD, Manson, JE, et al. Conjugated Equine Estrogens and Coronary Heart Disease: The Women's Health Initiative. Arch Intern Med 2006; 166:357.
7. Grodstein, F, Manson, JE, Stampfer, MJ. Hormone Therapy and Coronary Heart Disease: The Role of Time since Menopause and Age at Hormone Initiation. J Womens Health (Larchmt) 2006; 15:35.
8. Pinkerton, JV, Santen, R. Alternatives to the use of estrogen in postmenopausal women. Endocr Rev 1999; 20:308.
9. 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.
10. 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.
Fibroids
DEFINITION — Fibroids are growths of the uterus, or womb (show figure 1). They are also called uterine leiomyomas or myomas. They grow from the muscle cells of the uterus and may protrude from the inside or outside surface of the uterus. Fibroids may also be found within the muscular wall (show figure 2). Fibroids are not cancerous or pre-cancerous.
Fibroids are very common. At least 25 percent of women have signs of fibroids that can be detected by a pelvic examination, although not all women have symptoms.
CAUSES — Although the exact cause of fibroids is unknown, their growth seems to be related to the hormones estrogen and progesterone. When these hormone levels decrease at menopause, many of the symptoms of fibroids begin to resolve. However, it is not clear that hormones actually cause the fibroids. For example, women who have had high levels of both of these hormones as a result of pregnancy or birth control pills have a lower incidence of fibroids later in life.
RISK FACTORS — A number of factors influence the risk of developing fibroids. These include:
Ethnic background — Fibroids are three times more common in black women as compared to white, non-Hispanic women. In studies of women undergoing hysterectomy (removal of the uterus), black women were significantly more likely to have fibroids, were younger at the time of diagnosis and hysterectomy, and had more severe problems associated with fibroids as compared to white women.
Number of pregnancies — Women with one or more pregnancies that extended beyond 5 months have a decreased risk of fibroid formation.
Use of birth control — Women who use birth control pills have a lower risk of developing fibroids, although women who use the pill at an early age (between age 13 and 16) may have an increased risk. Similar to the birth control pill, women who use using continuous progestin contraceptives (for example, Depo Provera®) have a lower risk of fibroids. (See "Patient information: Contraception").
Smoking — Women who smoke appear to have a decreased risk of fibroids in some studies. However, any small benefit is clearly outweighed by the many serious health risks associated with cigarette smoking.
Diet — Significant consumption of beef, ham, or other red meats is associated with an increased risk of fibroids, while consumption of green vegetables decreases risk. However, no study has shown that changes in diet influence changes in the incidence or symptoms of fibroids. Women who consume alcohol, especially beer, have an increased risk of developing fibroids.
SYMPTOMS — The majority of fibroids are small and do not cause any symptoms at all. However, many women with fibroids have significant bleeding and/or pain that interfere with some aspect of their lives. The severity of symptoms is related to the number, size, and location of the fibroids, and fall into three main groups: increased uterine bleeding, pelvic pressure and pain, and problems related to pregnancy and fertility. As noted above, the symptoms tend to decrease at the time of menopause, although women who take hormone replacement may not see this effect.
Increased uterine bleeding — Fibroids can cause an increase in the amount of blood flow and length of a woman's menstrual period. The presence and amount of uterine bleeding is determined mainly by the location and size of the fibroid. Women with fibroids that protrude into the uterus are more likely to have significant increases in bleeding, although women with all types of fibroids can have this problem. If the bleeding is very heavy, anemia (low red blood cell count) can occur.
Bleeding irregularly (between periods) is not a characteristic of fibroids and may indicate another problem. Women with irregular bleeding should speak with their healthcare provider.
Pelvic pressure and pain — Fibroids can range in size from microscopic to the size of a grapefruit or even larger. Larger fibroids may cause a sense of pressure and fullness in the abdomen, similar to that caused by pregnancy. Fibroids of variable sizes can cause other symptoms, depending upon where they are located within the uterus. As an example, if the fibroid is pressing on the bladder, frequent urination or difficulty emptying the bladder can occur. A fibroid near the rectum may cause constipation, and cervical fibroids can cause pain during sexual intercourse.
In rare cases, fibroids can cause sudden and severe pain if the fibroid begins to break down (degenerate) or twist. Pain of this type may be associated with a mild fever, tenderness in the abdomen, and elevation in the white blood cell count. The pain usually resolves in a few days to weeks. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, can be used to treat the discomfort.
Problems with pregnancy and fertility — Some studies have suggested a slightly increased risk of problems during pregnancy in women with very large fibroids, including breech presentation, premature rupture of membranes, premature labor, and placental abruption (a condition in which the placenta separates prematurely from the uterine wall). In addition, women with very large fibroids are at a high risk of cesarean delivery. These problems are more likely if the placenta is implanted over the area of the large fibroid. Nevertheless, nearly all women with fibroids have completely normal pregnancies without complications. (See "Patient information: Cesarean delivery" and see "Patient information: Preterm labor").
The risk of miscarriage and infertility is associated with a type of fibroid that protrudes into the uterine cavity. Typically these fibroids can be easily removed using a hysteroscope (a small telescope-like device inserted through the cervix into the uterus), which reduces this risk.
However, it is not completely clear what role that fibroids play in infertility. An infertile woman who has large or numerous fibroids may want to talk with her doctor about having the fibroids removed, although all other causes of infertility should first be eliminated. (See "Patient information: Evaluation of the infertile couple").
DIAGNOSIS — Fibroids are often diagnosed during a routine pelvic exam. A clinician may feel the enlarged, irregular outline of the uterus through the abdomen. In certain cases, the clinician may wish to confirm the diagnosis of fibroids and exclude other types of masses. Ultrasound is generally preferred, and uses sound waves to visualize the uterus.
Hysterosalpingogram — A hysterosalpingogram (also called HSG or tubogram) may be recommended for a woman who is trying to become pregnant. During this test, an x-ray of the uterus and tubes is taken after dye is inserted through the cervix. The dye outlines the shape of the inside of the uterus and fallopian tubes. This test can diagnose the presence, size, and location of fibroids that may be protruding into the uterine cavity, and shows if the fallopian tubes are patent (open) (show picture 1).
Sonohysterogram — A sonohysterogram (also called SHG or saline-infusion sonogram), uses ultrasound to view the inside of the uterus while a saline solution is inserted through the cervix. This test is most useful in a woman with heavy or long periods who has had a normal pelvic ultrasound. It is possible for a fibroid or endometrial polyp to cause heavy bleeding, but not be visible with traditional ultrasound (show picture 2).
In some cases, the fibroids are found during X-ray, MRI, or ultrasound procedures that are done for another reason.
TREATMENT — In women who have no symptoms from their fibroids, treatment is usually not required. In women with significant symptoms, treatment may be medical or surgical.
Medical treatment — Medical treatment includes the use of medications to treat the symptoms of fibroid-related bleeding and pain. Gonadotropin-releasing hormone (GnRH) agonists are the most common medical treatment for fibroids. Leuprolide (Lupron Depot®) is an example of a GnRH agonist. Most women who use GnRH agonists temporarily stop having menstrual periods and have a significant reduction in the size of their fibroid(s). Reducing or eliminating menstrual bleeding can improve anemia.
However, fibroids rapidly enlarge after GnRH agonists are discontinued. In addition, there are some significant side effects after long-term use, including bone loss leading to osteoporosis. GnRH medications are usually given as a temporary measure (usually no longer than six months), such as while a woman is preparing for surgical treatment. In some cases, using a small dose of estrogen can minimize the side effects of GnRH agonists.
Danazol is an androgenic steroid, and may be used to stop menstrual bleeding. Danazol may be used when it is not necessary to shrink the size of the uterus or for women who cannot take GnRH-agonists. Use of Danazol is generally limited due to bothersome side effects, including weight gain and mood changes.
Surgical treatment — In most women, surgical treatment is used to provide relief from fibroid symptoms. In other cases, surgical procedures are done in an attempt to treat infertility. A number of surgical treatments are available.
Hysterectomy — Hysterectomy is surgical removal of the uterus through the abdomen or vagina. It may be the treatment of choice for some women who have completed childbearing, are not interested in other surgical treatments, and who have severe symptoms. Removal of the ovaries and cervix is not necessary for symptom relief. (See "Patient information: Abdominal hysterectomy").
Abdominal myomectomy — Myomectomy is surgical removal of a fibroid. In an abdominal myomectomy, an incision is made through the abdomen to expose the uterus, and the fibroids are excised from the uterine muscle. It is done in women who do not want to have a hysterectomy, and who have multiple fibroids or significant enlargement of the uterus. Blood loss, time off from work, and complications are similar to that seen with hysterectomy.
Myomectomy preserves the chance of future childbearing and may provide short-term relief of heavy bleeding, but is associated with a significant risk of recurrence. Between 10 and 25 percent of women who have myomectomy will require a second surgery. In addition, abdominal and laparoscopic myomectomy slightly increase the risk of uterine rupture during pregnancy or labor; the risk for most women is small.
Laparoscopic myomectomy — In this procedure, fibroids are removed through a laparoscope, a thin tube inserted through a small incision in the abdomen. A surgeon uses the laparoscope to visualize and remove the fibroids. Laparoscopic myomectomy requires a physician who is skilled in performing this technique, and is usually reserved for women with one or two small fibroids located on the outer surface of the uterus.
Hysteroscopic myomectomy — In this procedure, a telescope-like instrument (hysteroscope) is placed into the vagina, through the cervix and into the uterus. Fibroids may be seen through the hysteroscope and removed. This procedure can only be done on fibroids that are on the inside of the uterus, and it requires a physician who is skilled in performing this technique. This approach decreases menstrual bleeding with little reduction in uterine size.
Endometrial ablation — In this procedure, the lining of the uterus is destroyed with heat by a scope inserted into the vagina through the cervix and into the uterus. It can be done alone, or in combination with other treatments such as hysteroscopic myomectomy or myolysis (explained below). Pregnancy is possible, though not recommended after endometrial ablation; contraception is strongly recommended since a woman continues to ovulate. Endometrial ablation decreases bleeding without affecting uterine size.
Uterine artery embolization — In uterine artery embolization (UAE or UFE), a small catheter is inserted in a large blood vessel and threaded up to blood vessels near a fibroid (show figure 3A-3B). Tiny particles are injected into the blood vessel, which stops blood flow to the fibroid (show figure 4). This causes the fibroid to rapidly decrease in size within days to weeks after UAE.
The procedure appears to provide significant reduction in symptoms with few serious complications, although follow up data is limited to five years. The mean reduction in fibroid volume is comparable to that seen with GnRH-agonist treatment (30 to 40 percent). Post-procedure — Serious complications of UAE are rare, and similar to complications of other fibroid surgeries. Post-procedure pain is generally moderate to severe; most women stay in the hospital and receive intravenous pain medication after their procedure. Fever occurs in approximately one third of women, but is not usually related to infection. A small percentage of women (5 to 8 percent) stop having menstrual periods after UAE, which can be temporary or permanent. This change is more likely in women greater than 50 years of age; 40 percent of these women have no menstrual periods following UAE. Approximately 95 percent of women report significant improvement in symptoms and quality of life after UAE. Pregnancy after UAE — Pregnancy is not recommended for women who have undergone UAE, although normal pregnancies have occurred. UAE can affect ovarian function, potentially increasing the chances of infertility after treatment. Additionally, there is an increased risk of placental abnormalities in pregnancy following UAE. Myolysis — In this procedure, the fibroid tissue is destroyed through a laparoscope inserted in the abdomen. Myolysis can be combined with endometrial ablation, which is more effective than either procedure alone. Focused Ultrasound Surgery — MRI-guided focused ultrasound surgery (MRgFUS) is a new, FDA-approved treatment for fibroids. It involves destroying fibroid tissue with high intensity, focused ultrasound heat energy. The treatment takes place in an MRI machine, which gives live, "real-time" images of the uterus, allowing for progress to be monitored while the procedure is done. Only short-term outcome data is available, but MRgFUS appears to provide good symptom relief without incisions. In addition, it can be done on an outpatient basis. The treatment is not widely available since it is expensive, time consuming, and requires special equipment.
Choosing a treatment — In deciding on the best surgical treatment for fibroids, a number of factors should be considered. One of the most critical is whether or not childbearing has been completed. Although hysterectomy provides excellent relief of symptoms, a woman who wishes to become pregnant in the future may choose myomectomy. A woman who is done with childbearing but who is not interested in hysterectomy may consider uterine artery embolization, myolysis, endometrial ablation, or a combination of the above.
SUMMARY Fibroids are growths of the uterus (womb) (show figure 1 and show figure 2). Fibroids are not cancerous or pre-cancerous. The exact cause of fibroids is unknown (see "Risk factors" above). Most fibroids are small and do not cause any problems. Women with several small fibroids or one large fibroid often have heavy bleeding and/or pain during their menstrual period. This pain and bleeding can cause a woman to miss work or school (see "Symptoms" above). Fibroids may be diagnosed with a pelvic exam or ultrasound test (see "Diagnosis" above). Fibroids may need to be treated if the woman has heavy bleeding or pain. Women who do not have heavy bleeding or pain usually do not need any treatment. A medicine or surgery may be used to shrink the fibroid. Surgery to remove the fibroid or entire uterus is another option (see "Surgical treatment" above). The best type of treatment depends upon whether the woman wants to become pregnant in the future. Some treatments prevent pregnancy (see "Choosing a treatment" above).
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)
U.S. Department of Health and Human Services
(www.4woman.gov)
Society of Interventional Radiology
(www.sirweb.org, search for "uterine fibroids")
The Cochrane Collaboration
(www.cochrane.org, search for "uterine fibroids")
[1-9]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Cramer, SF, Patel, A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990; 94:435.
2. Parazzini, R, La Vecchia, C, Negri, E, et al. Epidemiologic characteristics of women with uterine fibroids: a case-control study. Obstet Gynecol 1988; 72:853.
3. Stewart, EA, Nowak, RA. New concepts in the treatment of uterine leiomyomas. Obstet Gynecol 1998; 92:624.
4. American College of Obstetricians and Gynecologists. Surgical alternatives to hysterectomy in the management of leiomyomas. ACOG practice bulletin #16, American College of Obstetricians and Gynecologists, Washington, DC 2000.
5. Iverson, RE Jr, Chelmow, D, Strohbehn, K, et al Relative morbidity of abdominal hysterectomy and myomectomy for management of uterine leiomyomas. Obstet Gynecol 1996; 88:415.
6. Spies, JB, Spector, A, Roth, AR, et al. Complications after uterine artery embolization for leiomyomas. Obstet Gynecol 2002; 100:873.
7. Pron, G, Bennett, J, Common, A, Wal,l J, Asch M, Sniderman K. The Ontario uterine fibroid embolization trial part 2. Uterine fibroid reduction and sympton relief after uterine artery embolization for fibroids. Fertil Steril 2003; 79:120.
8. Marshall, LM, Spiegelman D, Goldman, MB, Manson JE, Colditz GA, Barbieri RL, et al. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril 1998; 70:432.
9. ACOG Committee Opinion. Uterine artery embolization. Obstet Gynecol 2004; 103:403.
Fibroids are very common. At least 25 percent of women have signs of fibroids that can be detected by a pelvic examination, although not all women have symptoms.
CAUSES — Although the exact cause of fibroids is unknown, their growth seems to be related to the hormones estrogen and progesterone. When these hormone levels decrease at menopause, many of the symptoms of fibroids begin to resolve. However, it is not clear that hormones actually cause the fibroids. For example, women who have had high levels of both of these hormones as a result of pregnancy or birth control pills have a lower incidence of fibroids later in life.
RISK FACTORS — A number of factors influence the risk of developing fibroids. These include:
Ethnic background — Fibroids are three times more common in black women as compared to white, non-Hispanic women. In studies of women undergoing hysterectomy (removal of the uterus), black women were significantly more likely to have fibroids, were younger at the time of diagnosis and hysterectomy, and had more severe problems associated with fibroids as compared to white women.
Number of pregnancies — Women with one or more pregnancies that extended beyond 5 months have a decreased risk of fibroid formation.
Use of birth control — Women who use birth control pills have a lower risk of developing fibroids, although women who use the pill at an early age (between age 13 and 16) may have an increased risk. Similar to the birth control pill, women who use using continuous progestin contraceptives (for example, Depo Provera®) have a lower risk of fibroids. (See "Patient information: Contraception").
Smoking — Women who smoke appear to have a decreased risk of fibroids in some studies. However, any small benefit is clearly outweighed by the many serious health risks associated with cigarette smoking.
Diet — Significant consumption of beef, ham, or other red meats is associated with an increased risk of fibroids, while consumption of green vegetables decreases risk. However, no study has shown that changes in diet influence changes in the incidence or symptoms of fibroids. Women who consume alcohol, especially beer, have an increased risk of developing fibroids.
SYMPTOMS — The majority of fibroids are small and do not cause any symptoms at all. However, many women with fibroids have significant bleeding and/or pain that interfere with some aspect of their lives. The severity of symptoms is related to the number, size, and location of the fibroids, and fall into three main groups: increased uterine bleeding, pelvic pressure and pain, and problems related to pregnancy and fertility. As noted above, the symptoms tend to decrease at the time of menopause, although women who take hormone replacement may not see this effect.
Increased uterine bleeding — Fibroids can cause an increase in the amount of blood flow and length of a woman's menstrual period. The presence and amount of uterine bleeding is determined mainly by the location and size of the fibroid. Women with fibroids that protrude into the uterus are more likely to have significant increases in bleeding, although women with all types of fibroids can have this problem. If the bleeding is very heavy, anemia (low red blood cell count) can occur.
Bleeding irregularly (between periods) is not a characteristic of fibroids and may indicate another problem. Women with irregular bleeding should speak with their healthcare provider.
Pelvic pressure and pain — Fibroids can range in size from microscopic to the size of a grapefruit or even larger. Larger fibroids may cause a sense of pressure and fullness in the abdomen, similar to that caused by pregnancy. Fibroids of variable sizes can cause other symptoms, depending upon where they are located within the uterus. As an example, if the fibroid is pressing on the bladder, frequent urination or difficulty emptying the bladder can occur. A fibroid near the rectum may cause constipation, and cervical fibroids can cause pain during sexual intercourse.
In rare cases, fibroids can cause sudden and severe pain if the fibroid begins to break down (degenerate) or twist. Pain of this type may be associated with a mild fever, tenderness in the abdomen, and elevation in the white blood cell count. The pain usually resolves in a few days to weeks. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, can be used to treat the discomfort.
Problems with pregnancy and fertility — Some studies have suggested a slightly increased risk of problems during pregnancy in women with very large fibroids, including breech presentation, premature rupture of membranes, premature labor, and placental abruption (a condition in which the placenta separates prematurely from the uterine wall). In addition, women with very large fibroids are at a high risk of cesarean delivery. These problems are more likely if the placenta is implanted over the area of the large fibroid. Nevertheless, nearly all women with fibroids have completely normal pregnancies without complications. (See "Patient information: Cesarean delivery" and see "Patient information: Preterm labor").
The risk of miscarriage and infertility is associated with a type of fibroid that protrudes into the uterine cavity. Typically these fibroids can be easily removed using a hysteroscope (a small telescope-like device inserted through the cervix into the uterus), which reduces this risk.
However, it is not completely clear what role that fibroids play in infertility. An infertile woman who has large or numerous fibroids may want to talk with her doctor about having the fibroids removed, although all other causes of infertility should first be eliminated. (See "Patient information: Evaluation of the infertile couple").
DIAGNOSIS — Fibroids are often diagnosed during a routine pelvic exam. A clinician may feel the enlarged, irregular outline of the uterus through the abdomen. In certain cases, the clinician may wish to confirm the diagnosis of fibroids and exclude other types of masses. Ultrasound is generally preferred, and uses sound waves to visualize the uterus.
Hysterosalpingogram — A hysterosalpingogram (also called HSG or tubogram) may be recommended for a woman who is trying to become pregnant. During this test, an x-ray of the uterus and tubes is taken after dye is inserted through the cervix. The dye outlines the shape of the inside of the uterus and fallopian tubes. This test can diagnose the presence, size, and location of fibroids that may be protruding into the uterine cavity, and shows if the fallopian tubes are patent (open) (show picture 1).
Sonohysterogram — A sonohysterogram (also called SHG or saline-infusion sonogram), uses ultrasound to view the inside of the uterus while a saline solution is inserted through the cervix. This test is most useful in a woman with heavy or long periods who has had a normal pelvic ultrasound. It is possible for a fibroid or endometrial polyp to cause heavy bleeding, but not be visible with traditional ultrasound (show picture 2).
In some cases, the fibroids are found during X-ray, MRI, or ultrasound procedures that are done for another reason.
TREATMENT — In women who have no symptoms from their fibroids, treatment is usually not required. In women with significant symptoms, treatment may be medical or surgical.
Medical treatment — Medical treatment includes the use of medications to treat the symptoms of fibroid-related bleeding and pain. Gonadotropin-releasing hormone (GnRH) agonists are the most common medical treatment for fibroids. Leuprolide (Lupron Depot®) is an example of a GnRH agonist. Most women who use GnRH agonists temporarily stop having menstrual periods and have a significant reduction in the size of their fibroid(s). Reducing or eliminating menstrual bleeding can improve anemia.
However, fibroids rapidly enlarge after GnRH agonists are discontinued. In addition, there are some significant side effects after long-term use, including bone loss leading to osteoporosis. GnRH medications are usually given as a temporary measure (usually no longer than six months), such as while a woman is preparing for surgical treatment. In some cases, using a small dose of estrogen can minimize the side effects of GnRH agonists.
Danazol is an androgenic steroid, and may be used to stop menstrual bleeding. Danazol may be used when it is not necessary to shrink the size of the uterus or for women who cannot take GnRH-agonists. Use of Danazol is generally limited due to bothersome side effects, including weight gain and mood changes.
Surgical treatment — In most women, surgical treatment is used to provide relief from fibroid symptoms. In other cases, surgical procedures are done in an attempt to treat infertility. A number of surgical treatments are available.
Hysterectomy — Hysterectomy is surgical removal of the uterus through the abdomen or vagina. It may be the treatment of choice for some women who have completed childbearing, are not interested in other surgical treatments, and who have severe symptoms. Removal of the ovaries and cervix is not necessary for symptom relief. (See "Patient information: Abdominal hysterectomy").
Abdominal myomectomy — Myomectomy is surgical removal of a fibroid. In an abdominal myomectomy, an incision is made through the abdomen to expose the uterus, and the fibroids are excised from the uterine muscle. It is done in women who do not want to have a hysterectomy, and who have multiple fibroids or significant enlargement of the uterus. Blood loss, time off from work, and complications are similar to that seen with hysterectomy.
Myomectomy preserves the chance of future childbearing and may provide short-term relief of heavy bleeding, but is associated with a significant risk of recurrence. Between 10 and 25 percent of women who have myomectomy will require a second surgery. In addition, abdominal and laparoscopic myomectomy slightly increase the risk of uterine rupture during pregnancy or labor; the risk for most women is small.
Laparoscopic myomectomy — In this procedure, fibroids are removed through a laparoscope, a thin tube inserted through a small incision in the abdomen. A surgeon uses the laparoscope to visualize and remove the fibroids. Laparoscopic myomectomy requires a physician who is skilled in performing this technique, and is usually reserved for women with one or two small fibroids located on the outer surface of the uterus.
Hysteroscopic myomectomy — In this procedure, a telescope-like instrument (hysteroscope) is placed into the vagina, through the cervix and into the uterus. Fibroids may be seen through the hysteroscope and removed. This procedure can only be done on fibroids that are on the inside of the uterus, and it requires a physician who is skilled in performing this technique. This approach decreases menstrual bleeding with little reduction in uterine size.
Endometrial ablation — In this procedure, the lining of the uterus is destroyed with heat by a scope inserted into the vagina through the cervix and into the uterus. It can be done alone, or in combination with other treatments such as hysteroscopic myomectomy or myolysis (explained below). Pregnancy is possible, though not recommended after endometrial ablation; contraception is strongly recommended since a woman continues to ovulate. Endometrial ablation decreases bleeding without affecting uterine size.
Uterine artery embolization — In uterine artery embolization (UAE or UFE), a small catheter is inserted in a large blood vessel and threaded up to blood vessels near a fibroid (show figure 3A-3B). Tiny particles are injected into the blood vessel, which stops blood flow to the fibroid (show figure 4). This causes the fibroid to rapidly decrease in size within days to weeks after UAE.
The procedure appears to provide significant reduction in symptoms with few serious complications, although follow up data is limited to five years. The mean reduction in fibroid volume is comparable to that seen with GnRH-agonist treatment (30 to 40 percent). Post-procedure — Serious complications of UAE are rare, and similar to complications of other fibroid surgeries. Post-procedure pain is generally moderate to severe; most women stay in the hospital and receive intravenous pain medication after their procedure. Fever occurs in approximately one third of women, but is not usually related to infection. A small percentage of women (5 to 8 percent) stop having menstrual periods after UAE, which can be temporary or permanent. This change is more likely in women greater than 50 years of age; 40 percent of these women have no menstrual periods following UAE. Approximately 95 percent of women report significant improvement in symptoms and quality of life after UAE. Pregnancy after UAE — Pregnancy is not recommended for women who have undergone UAE, although normal pregnancies have occurred. UAE can affect ovarian function, potentially increasing the chances of infertility after treatment. Additionally, there is an increased risk of placental abnormalities in pregnancy following UAE. Myolysis — In this procedure, the fibroid tissue is destroyed through a laparoscope inserted in the abdomen. Myolysis can be combined with endometrial ablation, which is more effective than either procedure alone. Focused Ultrasound Surgery — MRI-guided focused ultrasound surgery (MRgFUS) is a new, FDA-approved treatment for fibroids. It involves destroying fibroid tissue with high intensity, focused ultrasound heat energy. The treatment takes place in an MRI machine, which gives live, "real-time" images of the uterus, allowing for progress to be monitored while the procedure is done. Only short-term outcome data is available, but MRgFUS appears to provide good symptom relief without incisions. In addition, it can be done on an outpatient basis. The treatment is not widely available since it is expensive, time consuming, and requires special equipment.
Choosing a treatment — In deciding on the best surgical treatment for fibroids, a number of factors should be considered. One of the most critical is whether or not childbearing has been completed. Although hysterectomy provides excellent relief of symptoms, a woman who wishes to become pregnant in the future may choose myomectomy. A woman who is done with childbearing but who is not interested in hysterectomy may consider uterine artery embolization, myolysis, endometrial ablation, or a combination of the above.
SUMMARY Fibroids are growths of the uterus (womb) (show figure 1 and show figure 2). Fibroids are not cancerous or pre-cancerous. The exact cause of fibroids is unknown (see "Risk factors" above). Most fibroids are small and do not cause any problems. Women with several small fibroids or one large fibroid often have heavy bleeding and/or pain during their menstrual period. This pain and bleeding can cause a woman to miss work or school (see "Symptoms" above). Fibroids may be diagnosed with a pelvic exam or ultrasound test (see "Diagnosis" above). Fibroids may need to be treated if the woman has heavy bleeding or pain. Women who do not have heavy bleeding or pain usually do not need any treatment. A medicine or surgery may be used to shrink the fibroid. Surgery to remove the fibroid or entire uterus is another option (see "Surgical treatment" above). The best type of treatment depends upon whether the woman wants to become pregnant in the future. Some treatments prevent pregnancy (see "Choosing a treatment" above).
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)
U.S. Department of Health and Human Services
(www.4woman.gov)
Society of Interventional Radiology
(www.sirweb.org, search for "uterine fibroids")
The Cochrane Collaboration
(www.cochrane.org, search for "uterine fibroids")
[1-9]
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