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)


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