Menopause In-Depth

Introduction

The ovaries contain between 200,000 and 400,000 follicles, tiny sacks that contain the materials needed to produce mature eggs, or ova. The ovaries produce two major female hormones: estrogen and progesterone.

The uterus is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus. The main function of the uterus is to nourish the developing fetus prior to birth.

Estrogen. Estrogens have an effect on about 300 different tissues throughout a woman's body:

• They are essential for the reproductive process and for the development of the female organs.
• Estrogens determine the characteristic female distribution of body fat on the hips and thighs, which develops during adolescence.
• They also are involved in tissues in the central nervous system (including the brain), the bones, the liver, and the urinary tract.

Estrogen has different forms:

• The most potent form is estradiol.
• The other important, but less powerful, estrogens are estrone and estriol.

Most of the estrogens in the body are produced by the ovaries, but they can also be formed by other tissues, such as body fat, skin, and muscle.

Progesterone. Progesterone, the other major female hormone, is necessary for thickening and preparing the uterine lining for the fertilized egg.

Menopause and Perimenopause

As a woman ages, her supply of eggs declines. Menopause occurs naturally after the woman's supply of follicles has been depleted and menstruation ends completely. (Menopause may also be induced if the ovaries are surgically removed.)

Perimenopause. Menopause does not occur suddenly. A period called perimenopause usually begins a few years before the last menstrual cycle. Some experts believe there are three stages in the transition:

• Early Stage. The beginning of perimenopause can begin in some women in their 30s, but most often it starts between ages 40 and 44. It is marked by changes in menstrual flow and in the length of the cycle. There may be sudden surges in estrogen.
• Middle Stage. In the middle cycle, periods become irregular but they are not skipped.
• Late Stage. In the late stages, women begin missing the periods until they finally stop. About 6 months before menopause estrogen levels drop significantly. The fall in estrogen triggers the typical symptoms of vaginal dryness and hot flashes (which can last from half a year to more than 5 years after onset of menopause).

Menopause. At the point at which menopause occurs, the following hormonal changes occur:

• Ovarian secretion of estrogen and progesterone ends.
• Once the ovaries have stopped producing estrogens, however, they still continue to produce small amounts of the male hormone testosterone, which can be converted to estrogen (estradiol) in body fat.
• In addition, the adrenal gland continues to produce androstenedione (a male hormone), which is converted to estrone and estradiol in the body fat.

Click the icon to see an image of the adrenal glands.

• The total estrogen produced after menopause, however, is far less than that produced during a woman's reproductive years.

The average age of women at menopause today is 51.4 years although it can occur as early as age 40 to as late as the early 60s. Women now have a life expectancy of more than 80 years. Currently, women can expect to live some 30 or 40 years of their life in the postmenopausal state.

Menopause is not a disease. However, many conditions are associated with estrogen depletion, including heart disease, osteoporosis, and other complications. Fortunately, effective treatments are available for these conditions.

In a number of studies, most women have reported menopause as a positive experience and have welcomed it with relief and as a sign of a new stage in life.

Complications

After a woman reaches menopause, her average life expectancy is 30 to 40 years. During those years, however, she faces certain health risks due to lower levels of estrogen that cause accelerated bone loss and an increase in LDL cholesterol (the so-called bad cholesterol). Her risks for serious disorders are estimated at 46% for heart disease, 20% for stroke, and 15% for hip fracture. In addition, about 8% of people over 75 have dementia, with postmenopausal women having 1.4 to three times the risk for Alzheimer's disease compared to men.

Menopause and Heart Health

Heart disease is the number one killer of women. In 2003, more than 480,000 women died from diseases of the heart and circulation (cardiovascular diseases). Although young women have a much lower risk for cardiovascular disease than young men, after menopause women catch up. After age 51, women’s risk of dying from heart disease is very close to that of men. Estrogen loss is believed to play a major role in this increased risk.

Some studies indicate that women who reach menopause at an early age are at increased risk of heart disease. However, recent research suggests that the reverse may also be true. A 2006 study suggested that women who have heart disease risk factors (smoking, high total cholesterol levels, high blood pressure) during premenopause may enter menopause earlier than women with healthier heart profiles.

Estrogen has the following effects:

• Positive Effects on Cholesterol and Other Lipids (Fats in the Blood). About 2 years before menopause, as estrogen levels begin to decline, the levels of the harmful low-density lipoprotein (LDL) cholesterol begin to rise and the advantageous high-density lipoprotein (HDL) levels decrease.
• Positive Effect on Blood Flow. Estrogen has significant effects on smoothing, relaxing, and opening blood vessels, thereby increasing blood flow and reducing pressure.
• Antioxidant Actions. Estrogen is also an antioxidant. That is, it helps clean up particles called oxygen-free radicals that are released by natural chemical processes in the body, which can cause significant damage, including harm to the arteries.
• Mixed Effects on Blood Pressure. The effects of estrogen on blood pressure are not clear. Oral contraceptives, for instance, which contain estrogen, appear to increase pressure slightly.

Blood pressure is the force applied against the walls of the arteries as the heart pumps blood through the body. The pressure is determined by the force and amount of blood pumped and the size and flexibility of the arteries.

• Mixed Effects on Blood Clotting. Estrogen affects many blood-clotting factors in the liver: It reduces blood viscosity (stickiness) and may enhance fibrinolysis, the natural process for breaking down blood clots. Unfortunately, estrogen also has other actions that increase the risk for blood clots. Women who take hormone replacement therapy are at risk for thromboembolism -- blood clots that block a vessel.

Click the icon to see an image of thromboembolism.

• This action may explain the higher rates of adverse heart events now observed in women with heart disease who take HRT.

Menopause and Bone Density

Osteoporosis is a disease of the skeleton in which bones become brittle and prone to fracture. In other words, the bone loses density. At age 65, about 30% of women have osteoporosis, and nearly all of them are unaware of their condition. After age 80, up to 70% of women develop osteoporosis. Osteoporosis is a major risk factor for fracture in the spine and hip. The lifetime risk of spinal fracture in women is about 1 in 3 and that for hip fracture is 1 in 6. Furthermore, between 10 - 20% of women who experience a hip fracture die within a year and about 25% require nursing home treatment.

Click the icon to see an image of osteoporosis.

Experts are still puzzled by the extreme speed-up of bone breakdown (resorption) after menopause. Estrogen may have an impact on bone density in various ways:

• Estrogen's most important effect on osteoporosis appears to be prevention of bone break down (resorption). Some research suggests that estrogen may control the life span of osteoclasts, the cells responsible for bone breakdown.
• Part of estrogen's beneficial actions may involve maintaining normal levels of vitamin D, an important nutrient in bone protection.

Risk factors for osteoporosis include:

• Being tall and thin
• Being Caucasian
• Smoking
• Taking thyroid hormone
• Being sedentary
• Early menopause or surgical menopause (removal of ovaries)

Women at risk for osteoporosis should have a bone density test to measure their bone mass and then make a decision about treatment after consulting their doctor.

Menopause and Depression

Depression may occur as a woman transitions into menopause (perimenopause), even among women with no history of clinical depression. Hormonal changes and declines in estrogen levels are probably involved in this process. Research suggests that a depressive disorder is 2.5 times more likely to develop during perimenopause than premenopause. Women who transition to menopause at a younger age are at increased risk of a first episode of depression.

Symptoms of clinical depression include:

• Loss of interest or pleasure in activities once enjoyed
• Persistent (longer than 2 weeks) sad mood
• Decreased energy
• Sleep problems (insomnia or oversleeping)
• Feelings of guilt, worthlessness, and hopelessness
• Difficulty concentrating

Some of these symptoms may overlap with other symptoms that typically accompany perimenopause. Women who experience these symptoms should talk to their doctor. Depression is treatable. [For more information, see In-Depth Report #8: Depression.] For many women, depression eases once they reach menopause.

Estrogen Loss and Mental Decline

Estrogen, the primary female hormone, appears to have properties that protect against the memory loss and lower mental functioning associated with normal aging. Estrogen's effects on the brain include:

• Laboratory studies suggested that estrogen may help block production of beta-amyloid, the source of the sticky plaques found in Alzheimer's brains.
• Estrogen may trigger the temporary growth of nerve pathways in the memory portion of the brain.
• Estrogen may stimulate production of the neurotransmitters acetylcholine and serotonin, which are depleted in Alzheimer's patients.
• Estrogen also appears to smooth, relax, and open blood vessels, which may help blood flow in the brain.
• Estrogen is an antioxidant. That is, it helps clean up free-oxygen radicals, the unstable particles thought to play a role in Alzheimer's.
• Studies have been mixed on the association between natural estrogen levels and mental functioning in older women.

Gum Disorders and Tooth Loss

Estrogen therapy has been associated with reduced gum bleeding and with decreased bone loss around the teeth, and women who take estrogen are less likely to lose their teeth. Thus, the same principle that helps prevent bone loss in osteoporosis is also at work in preventing bone loss in the mouth.

Eye Disorders

Estrogen, progesterone, or both appear to protect against cataracts.

Click the icon to see an image of a cataract.

Studies are also indicating that estrogen helps prevent glaucoma and macular degeneration.

Click the icon to see an image of glaucoma.

Click the icon to see an image of macular degeneration.

Urinary Incontinence

The drop in body estrogen levels brought on by menopause may contribute to both urinary stress and urge incontinence.

Urinary Tract Infections

Women are at increased risk for recurrent urinary tract infections after menopause. Research suggests that estrogen may prevent infection by increasing the number of lactobacilli, a microorganism that fights infection by preventing bacteria from adhering to vaginal cells.

Wrinkles

Some evidence suggests that estrogen may help prevent slackness and dryness in the skin and reduce wrinkles.

Sleep Disorders

Menopause is associated with more sleeping problems, including inability to fall asleep and nighttime wakefulness.

Symptoms

The most prominent symptoms of the transition to menopause include:

• Hot flashes and night sweats. Women often experience hot flashes as an intense build-up in body heat, followed by sweating and chills. Some women report accompanying anxiety as the sensation builds. In most cases hot flashes resolve within 2 years of menopause, although in some women they may persist for years. Women who have a hysterectomy (surgical removal of the uterus) are less likely to experience hot flashes than women who have a natural menopause. However, women who have surgical removal of both ovaries, and who do not receive hormone replacement therapy, may have more severe hot flashes than women who enter menopause naturally.
• Heart pounding or racing can occur, with or without hot flashes.
• Difficulty sleeping. Insomnia is common during perimenopause. It may be caused by the hot flashes or it may be an independent symptom of hormonal changes.
• Mood changes. Mood changes are most likely to be a combination of sleeplessness, hormonal swings, and psychologic factors as a woman undergoes this intense passage in her life. Once a woman has reached a menopausal state, however, depression is no more common than before, and women with a history of premenstrual depression often experience significant mood improvement.
• Sexuality. Sexual responsiveness tends to decline in most women after menopause, although other aspects of sexual function, including interest, frequency, and vaginal dryness vary. It is useful to remember that the symptoms of menopause eventually go away.
• Forgetfulness. This appears to be one of the few symptoms that are common across most cultural and ethnic groups.
• Urine leakage.
• Vaginal dryness.
• Joint stiffness.

Women from different ethnic and or cultural groups report different menopausal symptoms. For example, in one study hot flashes occurred in about 30% of Caucasians and 45% of African Americans. Hispanic women tended to complain of urine leakage, vaginal dryness, and heart pounding. Japanese and Chinese women experienced far fewer menopausal symptoms, except for forgetfulness. All groups complained about this symptom.

Lifestyle Changes

Simple changes in lifestyle and diet can help control menopausal symptoms such as hot flashes. Avoid hot flash triggers like spicy foods, hot beverages, caffeine, and alcohol. Dress in layers so that clothes can be removed when a hot flash occurs. For vaginal dryness, moisturizers, and non-estrogen lubricants, such as KY Jelly, Replens, and Astroglide are available.

Healthy Diet

When women reach menopause, they are at increased risk for heart disease. A heart-healthy diet is an important way to control cholesterol and blood pressure levels. Everyone should maintain a healthy diet rich in fresh fruits, vegetables, whole grains, and low in saturated fats (found in dairy and animal products) and trans-fatty acids (found in shortening, commercial baked goods, and hard margarines). Reducing salt intake is also important as people age. [For more information, see In-Depth Report #42: Heart-healthy diet.]

Vegetables, fruits, whole grains, nuts, and legumes (beans and peas) contain fiber and many nutrients that are important for the heart and overall health. Vitamin supplements are not recommended in place of healthy foods. Research increasingly suggests that high vitamin doses may have harmful effects.

Mineral-Rich Fruits and Vegetables. Diets rich in fresh fruits and vegetables are high in potassium and magnesium and can help preserve bones and protect against heart disease. Potassium-rich fruits include bananas, oranges, prunes, and cantaloupes, and vegetables that contain potassium include carrots, spinach, celery, alfalfa, mushrooms, lima beans, potatoes, avocados and broccoli. Foods rich in magnesium include dairy products, spinach, potatoes, beets, nuts, sole, and halibut.

Avoid Fast Foods and Limiting Salts. Reducing salt is important for protecting both the heart and the bones. High sodium intake interferes with calcium retention. Limiting table salt is not sufficient, since most salt in the Western diet comes from fast foods and commercial food products. Such foods are often also high in dangerous fats called trans-fatty acids that are harmful to the heart.

Effects of Fiber. Fiber is important for the heart. Some studies report estrogen loss with high amounts of wheat bran (but not oat or corn) and calcium loss with any high-fiber diet. Calcium supplements can help offset this effect.

Healthy Protein Sources. The American Heart Association (AHA) recommends soy, legumes, poultry, and lean meats as good protein sources and recommends eating fish at least twice a week. Soy is an excellent food. It is rich in both soluble and insoluble fiber, omega-3 fatty acids, and provides all essential proteins. Soy proteins have more vitamins and minerals than meat or dairy proteins. They also contain polyunsaturated fats, which are better than the saturated fat found in meat. The best sources of soy protein are soy products (tofu, soy milk, soybeans).

For many years, soy was promoted as a food that could help lower cholesterol and improve heart disease risk factors. But an important 2006 review of studies found that soy protein and isoflavone supplement pills do not really have any effects on cholesterol or heart disease prevention. The AHA still recommends soy foods, but not supplements, as a healthy food choice. The benefits of soy on menopausal symptoms are mixed (see below in Alternative Therapies).

Soy is high in estrogen-like plant chemicals called isoflavones, which may improve bone health in older women. A 2005 review of 15 clinical trials found that, although the results were mixed, isoflavones appeared to decrease bone loss, especially in younger postmenopausal women. Soy food products, such as tofu, that also contain calcium may be particularly beneficial.

Calcium and Vitamin D

Calcium. Women should be sure they have sufficient calcium and vitamin D in their diet by consuming low-fat dairy products or calcium-enriched orange juice. The standard recommended dose for older people is between 1000 and 1500 mg per day, depending on risk factors. Even doses of 1000 mg may help preserve bone in many postmenopausal women without osteoporosis, especially during winter months (when bone loss is greatest). In women who have already experienced osteoporosis-related fractures, however, 1000 mg daily may not add any protective benefits without bone-building medication. Calcium citrate (Citracal) is better absorbed than many other calcium compounds and was the first reported calcium supplement to preserve bone density after menopause.

Click the icon to see an image of the benefits of calcium.

High doses (over 2,500 mg per day) of calcium supplements may increase the risk for kidney stones. (Because many commercial foods are now fortified with calcium, this upper limit may be easier to reach than people think.)

Click the icon to see an image of calcium sources.

Vitamin D. Vitamin D is necessary for the absorption of calcium in the stomach and gastrointestinal tract and is the essential companion to calcium in maintaining strong bones. Some studies suggest that vitamin D protects against osteoporosis only in combination with calcium.

Vitamin D is manufactured in the skin using energy from the ultraviolet rays in sunlight. It can also be obtained from dietary supplements. As a person ages, vitamin D levels decline. They also fall during winters months and when people have inadequate sunlight. Pollution may also contribute to less sunlight and declining vitamin D levels.

Click the icon to see an image of vitamin D sources.

Current adult guidelines recommend:

• 400 IU (10 mcg) for people between ages 50 and 60
• 600 IU (15 mcg) for those over age 70 who do not have sufficient exposure to sunlight

Drinking milk fortified with vitamin D and sunlight exposure supply most people's need for vitamin D. (One cup of whole milk provides about 100 IU of vitamin D.) Oily fish (sardines especially, also salmon, fresh tuna, mackerel) are also important dietary sources of vitamin D.

Alcohol

Effect on the Heart. One drink a day in women who are not at risk for alcohol abuse may be beneficial for the heart. Red wine in particular contains a substance called resveratrol, which is classified as a phytoestrogen and has estrogen-like effects.

Effect on Bones. Alcohol has different effects on bones depending on how much is consumed. A 2004 study found that moderate wine consumption was linked to improved bone mineral density in postmenopausal women. Alcohol, in moderate amounts, may increase estrogen levels. Excessive drinking, however, has been associated with brittle bones.

Effect on Breast Cancer. Women who drink face an increased risk for breast cancer, but the risk associated with mild to moderate drinking is small.

Controlling Weight Gain

Many women need to increase physical activity and reduce caloric intake before and after menopause. Weight gain is common during these years, and it can be sudden and distressing, particularly when habitual exercise and eating patterns are no longer effective in controlling weight. Gaining weight around the abdomen (the so-called apple shape) is a specific risk factor for heart disease and diabetes and many other health problems.

Click the icon to see an image of different types of weight gain.

Exercise

For protection against all aging diseases, women, whether or not they are taking hormone replacement therapy, should pursue a lifestyle that includes a balanced aerobic and weight resistance exercise program appropriate to their age and medical conditions. Brisk walking, stair climbing, hiking, dancing, and tai chi are all helpful. Several studies report that exercise can help control hot flashes. A healthy diet plus regular, consistent exercise can also help ward off the weight gain associated with the menopause. Weight-bearing exercises are specifically helpful for protecting against bone loss.

Quit Smoking

If a woman smokes, she should quit. Smoking is linked to a decline in estrogen levels. Women who smoke experience menopause about 2 years earlier than nonsmokers. Smoking doubles a woman’s odds of developing coronary heart disease and is a major risk factor for osteoporosis.

Alternative Therapies

There are many unproved methods for relieving menopausal symptoms, some more effective than others. Acupuncture, meditation, and relaxation techniques are all harmless ways to reduce the stress of menopause and some people report great benefit from these practices.

Acupuncture, hypnosis and biofeedback are all alternative ways to control pain. Acupuncture involves the insertion of tiny sterile needles, slightly thicker than a human hair, at specific points on the body.

Women often try herbal or so-called natural remedies. Some may have proven benefits, but others have no value and can have adverse side effects.

Many studies have researched plant estrogens (phytoestrogens), which are generally categorized as isoflavones (found in soy and red clover) and lignans (found in whole wheat and flaxseed). No evidence to date indicates that phytoestrogen supplements provide any benefit for hot flashes or other menopausal symptoms. Nevertheless, foods containing them may be healthful.

Supplements containing specific isoflavones found in soy -- typically the estrogen-like compounds genistein and daidzein -- do not appear to provide any benefits compared to the whole soy protein. Taking them separately may, in fact, cause harm, including a possible increase in estrogen-related cancers.

The following herbs are sometimes use for menopausal symptoms and carry certain risks:

• Black cohosh (Cimicifuga racemosa), also known as squaw root, is the herbal remedy most studied for menopausal symptoms. Although it contains a plant estrogen, this substance does not act like an estrogen in the human body. Studies show mixed results in preventing hot flashes. Black cohosh has been used for decades in Germany and appears to be safe. Headaches and gastrointestinal problems are common side effects.
• Dong quai (Angelica sinensis) does not appear helpful for hot flashes or other menopausal symptoms. Do not use dong quai with blood-thinning drugs, such as warfarin, because it may cause bleeding complications.
• Ginseng (Panax ginseng) may help menopausal symptoms of depression and sleep problems, but it has no effect on hot flashes.
• Kava (Piper methysticum) may relieve anxiety but it does not help hot flashes. This herb is generally considered unsafe, due to several reports of liver failure and death, especially in people with liver disease.
• Wild yam (Dioscorea villosa) is an herb sometimes used for menstrual problems as well as menopausal symptoms. It contains a plant progesterone. However, like black cohosh, there is no evidence that the human body can convert this substance into a hormone. Patients should be aware that some commercial herbal wild yam products contain prescription progesterones.
• Dehydroepiandrosterone (DHEA) is a weak male hormone secreted by the adrenal gland. It is available as a dietary supplement. DHEA has no benefit for hot flashes and may increase the risk of breast cancer.

Medications

Hormone Replacement Therapy (HRT)

Doctors used to believe that HRT could help reduce the risk of heart disease and other health risks in addition to treating menopausal symptoms. The results of an important study, called the Women's Health Initiative (WHI), led doctors to revise their recommendations regarding HRT.

The WHI, started in 1991, enrolled 161,809 women between the ages of 50-79 in 40 different medical centers. Part of the study was intended to examine the health benefits and risks of hormone replacement therapy, including the risks of breast cancer, heart attacks, strokes, and blood clots.

In 2002, one component of the WHI, which studied the use of estrogen and progestin in women who had a uterus, was stopped early because the health risks exceeded the health benefits. The main reason for stopping the estrogen-progestin study was a 26% increase in breast cancer. This combination therapy study also showed an increased risk for heart attack, stroke, blood clots, and dementia. There was a reduced risk for colorectal cancer and bone fractures but these benefits did not outweigh the considerable risks.

In 2004, a second component of the WHI, which studied estrogen-only therapy in women who no longer have a uterus, was stopped early. This was primarily because of an increase in the risk for strokes and blood clots. The study also found the estrogen-only therapy had no effect on heart attack or colorectal cancer risk. An update in 2006 suggested that estrogen-only therapy does not increase breast cancer risk over the short term (average 7 years) but may increase risk when taken for a longer time (15 years or more).

While the WHI study suggests that HRT should not be prescribed for prevention of chronic diseases, many doctors still accept its use for short-term treatment of moderate to severe hot flushes and other menopausal symptoms, and in women undergoing premature menopause for medical or other reasons. Current guidelines recommend using the lowest possible dose for the shortest duration of time.

Hormones Used in HRT. Hormone replacement therapy uses either estrogen alone (known as ET or unopposed estrogen) or in combination with forms of progesterone (known as combined hormone therapy or EPT). Progesterone is referred to by one of several names:

• Progesterone is the name for the natural hormone
• Progestin is the term for any hormone, natural or synthetic, that causes progesterone effects
• Progestogen is any hormone that has effects similar to progesterone

Both ET and EPT are available in many forms, including oral tablets, skin patches, and vaginal and skin applications. A new form approved by the FDA in 2004 is a topical estrogen gel which is applied to the arm.

Menopausal Symptoms and HRT. HRT is mainly recommended for relieving menopausal symptoms, including vaginal atrophy and dryness, hot flashes, sleep problems, and mild depression. HRT does not prevent certain other problems associated with menopausal changes such as thinning hair.

Oral hormonal medications and skin patches are equally effective in reducing hot flashes, mild depression, and sleep problems. Progestins may sometimes be prescribed alone for hot flashes and other acute menopausal symptoms, though they can cause side effects, such as mood swings, bloating, and breast tenderness. Estrogen creams, rings, or vaginal tablets restore vaginal elasticity and lubrication and improve sexual pleasure.

Osteoporosis and HRT. HRT may be useful for some women at high risk for osteoporosis, although other drugs, such as bisphosphonates, should be considered first. It increases bone density and also appears to improve balance and protects against falling. Studies also report reductions in fractures (especially hip fractures) among women taking HRT, but the benefits may not outweigh the risks of HRT. It appears that the beneficial effects wear off soon after therapy is stopped. Estrogen must be taken life long for maximum protection against osteoporosis, which then increases the risk for adverse health effects.

Adverse Effects of HRT.

• Heart Disease. In spite of estrogen's benefits on cholesterol levels and other factors that affect the heart, evidence suggests that HRT does not prevent heart disease. In fact, it may actually be harmful for women with existing heart disease, at least in the first few years, and may also worsen the outlook after a heart attack. However, a 2004 review of 30 studies found that HRT does not significantly impact mortality from cardiovascular disease.
• Stroke. Studies have reported a slightly increased risk of stroke in women taking HRT within the first two years of treatment and in HRT users with a history of major stroke or small strokes (transient ischemic attacks). A 2005 review found that HRT increased the risk of stroke, particularly ischemic (a type of stroke caused by an interruption in blood flow to part of the brain) stroke. In addition, HRT appears to worsen the outlook for women who have had a stroke.
• Mental Decline. Observational studies had suggested that hormone replacement therapy (HRT) helped prevent mental decline and even Alzheimer's disease after menopause. Other studies have found no differences in mental performance and no protection from Alzheimer's disease in women taking HRT compared to non-users. A 2004 review of the Women’s Health Initiative Memory Study found that combined HRT did not reduce the risk of cognitive impairment, and actually increased the risk of dementia among women ages 65 and over.
• Thromboembolism. HRT is associated with a higher risk for thromboembolism, in which blood clots form in deep veins. This places women at risk for pulmonary embolism, in which the blood clot travels to the lungs.

Click the icon to see an image of a pulmonary embolism.

• Breast Cancer. Because breast tissue growth is highly sensitive to estrogens, the more a woman is exposed to estrogen over her lifetime, the higher the risk for breast cancer. A number of studies have now reported a higher risk for breast cancer in postmenopausal women taking HRT that contains both estrogen and progestin. A 2005 study suggested that HRT with no or low progestin is safer than standard combination therapy. Several 2006 studies of women who had a hysterectomy indicated that estrogen alone does not increase overall breast cancer risk when the drug is used for 7 years or less. However, women who take the drug for 15 years or more do have an increased risk. Women who are at low risk for breast cancer tend to have fewer breast cancers with estrogen alone, while women at higher risk tend to have more breast cancers. In addition, estrogen therapy may cause abnormal mammogram results. Breast tissue density increases with HRT, which makes mammograms more difficult to read and leads to more breast biopsies. Women who take estrogen HRT should be aware that they need frequent mammogram screenings.
• Endometrial (Uterine) Cancers. Estrogen overstimulates the tissue lining the uterus (the endometrium) and causes uncontrolled cell growth, a condition known as hyperplasia, which is a strong risk factor for cancer. Taking unopposed estrogen replacement therapy (ERT) increases the risk of endometrial cancer at least five-fold. Adding progestin to HRT appears to pose no risk for this cancer.
• Ovarian Cancer. Whether HRT increases the risk for ovarian cancer is unclear, although evidence does seem to suggest a higher risk with the use of unopposed estrogen. Short term used of combined HRT in one study did not increase the incidence of ovarian cancer. Another study reported that women who had used unopposed estrogen or HRT with sequential use (but not continuous use) of progestins were at higher risk. Studies to date, however, have been limited. (Ovarian cancer is very uncommon, with the mortality rate being 43 out of every 100,000 women. Even among long-term HRT users this rate increases only to 64.)
• Gallstones. HRT is associated with a higher risk for gallstones.

Other Drugs Used for Menopausal Symptoms

Despite its risks, hormone replacement therapy appears to be the best treatment for hot flashes. Nonhormonal treatments for hot flashes and other menopausal symptoms include:

Antidepressants. The antidepressants known as selective serotonin-reuptake inhibitors (SSRIs) are sometimes used for managing mood changes and hot flashes. They include fluoxetine (Prozac), sertraline (Zoloft), venlafaxine (Effexor), and paroxetine (Paxil, Asimia). A 2006 review of nonhormonal therapies, found that paroxetine in particular may help hot flashes. However, paroxetine, like other antidepressants, can cause headache, anxiety, and sexual problems.

Gabapentin.Several small studies suggest that gabapentin (Neurontin), a drug used for seizures and nerve pain, may relieve hot flashes. Gabapentin may cause drowsiness, dizziness, fatigue, and swelling of the hands and feet.

Clonidine. Clonidine (Catapres) is a drug used to treat high blood pressure. Studies show it may help manage hot flashes. Side effects include dizziness, drowsiness, dry mouth, and constipation

Testosterone. Some doctors prescribe combinations of estrogen and small amounts of the male hormone testosterone to improve sexual function and increase bone density. Side effects of testosterone include increased body hair, acne, fluid retention, anxiety, and depression. It also adversely affects cholesterol and lipid levels. Long-term benefits or other risks are unknown.

Drugs to Prevent and Treat Osteoporosis

After menopause, a woman is at increased risk osteoporosis. Certain drugs may be prescribed to help prevent bone loss. [For more information on osteoporosis prevention and treatment, see In-Depth Report #18: Osteoporosis.]

Selective Estrogen-Receptor Modulators (SERMs). SERMS are designed to produce the benefits of estrogen, such as bone protection, without its risks. They are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others.

The only SERM prescribed for menopausal conditions is raloxifene (Evista). It is prescribed for prevention and treatment of osteoporosis in post-menopausal women. Raloxifene also decreases LDL ("bad") cholesterol levels, but does not appear to increase HDL ("good") cholesterol.

Bisphosphonates. Bisphosphonates help increase bone mass, and are among the primary drugs against osteoporosis in postmenopausal women and in people taking corticosteroids or hormonal drugs that suppress estrogen. They are proving to reduce the risk of both spinal and hip fractures in women who have had prior bone breaks. The standard bisphosphonates include alendronate (Fosamax) and risedronate (Actonel).

Calcitonin. Produced by the thyroid gland, natural calcitonin regulates calcium levels by inhibiting the osteoclastic activity, the breakdown of bone. The drug version is derived from salmon and is available as a nasal spray (Miacalcin) and in injected form (Calcimar). Calcitonin is not used to prevent osteoporosis; it is used to treat osteoporosis. Calcitonin may be an alternative for patients who cannot take a bisphosphonate or SERM. It also appears to help relieve bone pain associated with established osteoporosis and fracture.

Low-Dose Parathyroid Injections. Although high persistent levels of parathyroid hormone can cause osteoporosis, daily injections of this hormone stimulate bone production. Unlike most treatments for osteoporosis, including bisphosphonates, the benefits may persist even after the injections have been stopped. Teriparatide (Forteo), a drug made from selected amino acids found in parathyroid hormone, is approved for treatment of osteoporosis in postmenopausal women. Studies suggest it may lower the risk of fracture and increase bone mineral density. In one small study, parathyroid significantly reduced spinal fractures compared to hormone replacement therapy.

Drugs to Prevent and Treat Heart Disease

Statins are the most effective drugs for treatment of unhealthy cholesterol levels and are now strongly recommended as the first choice for lipid-lowering treatment for older women with heart disease. Brands include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor). A major analysis of over 200 studies found that statins reduced the risk for heart problems by 60% and stroke by 17%. A 2005 review found that the more that statins lower LDL, the more they reduce CAD and other heart disease risks.

Lots More Information

Resources

• www.menopause.org -- North American Menopause Society
• www.nof.org -- National Osteoporosis Foundation
• www.acog.com -- American College of Obstetricians and Gynecologists
• www.nia.nih.gov -- National Institute on Aging
• www.nih.gov/PHTindex.htm -- National Institutes of Health -- Menopausal Hormone Therapy Information
• http://nccam.nih.gov/health/menopauseandcam -- National Center for Complementary and Alternative Medicine

References

Chen WY, Manson JE, Hankinson SE, Rosner B, Holmes MD, Willett WC, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med. 2006;166(9):1027-1032.

Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry. 2006;63(4):385-390.

Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006;63(4):375-382.

Gallicchio L, Whiteman MK, Tomic D, Miller KP, Langenberg P, Flaws JA. Type of menopause, patterns of hormone therapy use, and hot flashes. Fertil Steril. 2006;85(5):1432-1440.

Kok HS, van Asselt KM, van der Schouw YT, van der Tweel I, Peeters PH, Wilson PW, Pearson PL, Grobbee DE. Heart disease risk determines menopausal age rather than the reverse. J Am Coll Cardiol. 2006;47(10):1976-1983.

Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, Nicolaidis C, Walker M, Humphrey L. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295(17):2057-2071.

Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295(14):1647-1657.

Tice JA, Grady D. Alternatives to estrogen for treatment of hot flashes: are they effective and safe? JAMA. 2006 May 3;295(17):2076-8.