Menopause

Description

Alternative Names

Medications

Statins inhibit the liver enzyme hMG-CoA reductase, which is used in the manufacturing of cholesterol. They may also benefit the heart by mechanisms beyond lowering cholesterol levels, but what these are exactly is as yet unknown. They are the most effective drugs for the treatment of high cholesterol and are now strongly recommended as the first choice for lipid-lowering treatment for older women with heart disease. They may have other benefits for women as well.

Specific Statin Drugs. The statins include the two groups:

• So-called natural statins, including lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor). The natural statins are generally administered once a day; they should be taken in the evening because most cholesterol synthesis occurs between midnight and 3 AM. If more intensive treatment is required, a second, morning dose may be administered.
• Newer statins are fluvastatin (Lescol) atorvastatin (Lipitor), and rosuvastatin (Crestor). Some are taken twice a day. The newer agents may reduce LDL more effectively at equal doses to the natural statins, but more research is needed to confirm this.

All are effective and safe. All are approved for lowering LDL. Although at this time only lovastatin and pravastatin are approved for prevention of heart disease and stroke, studies are showing the same benefits in the others. The differences among them are currently under investigation.

Benefits of Statins. Their potential benefits for older women are the following:

• Heart Disease. Evidence now reports that statins effectively reduce the risk of major coronary events, including first and second heart attacks, in women as well as men with evidence of heart disease. Of particular interest was a 2002 study indicating that statins may help reduce the risk for heart events posed by HRT. Experts estimate a 25% to 30% reduction in mortality rates when patients take statins after a heart attack. (Some believe the decrease may even be greater.) And major studies published in 2002 reported that statins reduced mortality rates significantly in patients with heart disease or heart risk factors, regardless of whether or not cholesterol levels were high.

A heart attack or acute myocardial infarction (MI) occurs when one of the arteries that supplies the heart muscle becomes blocked. Blockage may be caused by spasm of the artery or by atherosclerosis with acute clot formation. The blockage results in damaged tissue and a permanent loss of contraction of this portion of the heart muscle.

• Stroke. Statins may also reduce the risk for stroke in patients with active heart disease and moderately high lipid levels. (Only the natural statins have been studied, and their effect on stroke in patients with other risk factors is not yet known.)

Click the icon to see an image of stroke.

• Osteoporosis. There have been some reports and animal studies suggesting that statins may protect against bone loss in older women. It is not clear, however, if the statins themselves have properties that prevent osteoporosis or if any other cholesterol-lowering agents might be helpful. Few clinical trials have been published, to date, and more work is needed to confirm any effect on bones.
• Mental Decline. Of considerable interest are a number of studies now reporting a significantly lower risk for Alzheimer's disease in people who were taking specific statins. Those showing promise include lovastatin (Mevacor), pravastatin (Pravachol), and atorvastatin (Lipitor.) Other statins have not been associated with a lower risk for Alzheimer's. In fact, some researchers are concerned that certain statins that cross the blood-brain barrier may actually worsen Alzheimer's in people who already have it.

Adverse Effects of Statins. Side effects include gastrointestinal discomfort, headaches, skin rashes, muscle aches, sexual dysfunction, drowsiness, dizziness, nausea, constipation, and peripheral neuropathy (numbness or tingling in the hands and feet). Statins can affect the liver, so periodic liver function tests should be administered. They can also injure muscle tissue, particularly when combined with fibrates (other cholesterol lowering drugs). The risk, however, is very low compared to their benefits. Statins should never be taken by anyone with liver problems or by women during pregnancy or breast-feeding.

Statins may have some adverse interactions with other drugs, including other cholesterol-lowering agents. Grapefruit juice and sour oranges (found in marmalades and other condiments, not in juice) may increase their potency.

Selective Estrogen-Receptor Modulators (SERMs)

Drugs known as selective estrogen-receptor modulators (SERMs) have been 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.

Currently available SERMs include raloxifene (Evista) and tamoxifen (Nolvadex). Tibolone (Livial) is a synthetic hormone that acts more like a progestin. It has minimal side effects and patient compliance in clinical trials has been high. It is not yet available in the US. Other SERMs under investigation include lasofoxifene. They all have some common properties but may vary according to benefits and adverse effects.

Osteoporosis and SERMs. Raloxifene (Evista) is the first SERM to be approved for preventing spinal fractures. (It does not appear to have any protective effect on other fractures, including those in the hip.) Raloxifene appears to have fewer side effects than hormone replacement therapy and women tend to stay on it. Low-dose tamoxifen may reduce the risk for fractures, but it has not been approved for this purpose.

Heart Disease and SERMs. Raloxifene may have some benefits on cholesterol levels. A 2002 study further reported possible heart protection in women with existing heart disease, although the findings could have been due to chance. SERMs still pose a risk for deep vein blood clots, which may have long-term implications on heart problems. Longer studies are needed on possible risks and benefits.

Breast Cancer and SERMs. Tamoxifen (Nolvadex) is the best-studied SERM and is now being used to prevent breast cancer in high-risk women and to prevent recurrence in women who have been treated for breast cancer. A major on-going study on raloxifene also reported a reduced risk for breast cancer of 72% over a four-year period.

Common Side Effects. Most SERMs do not relieve menopausal symptoms, and some exacerbate them. As with estrogen therapy, most SERMs increase the risk for blood clots. Tamoxifen, but not raloxifene, increases risk for uterine cancer. Tamoxifen is associated with worse mental function. Raloxifene studies are mixed, with an important 2001 study reporting no benefits.

Bisphosphonates

The bisphosphonates inhibit osteoclast activity, increase bone mass, and are among the primary drugs against osteoporosis in postmenopausal women and in people taking corticosteroids or hormonal agents that suppress estrogen. They are proving to reduce the risk of both spinal and hip fractures in women who have had prior bone breaks.

Brands. A number of bisphosphonates in different forms are available or under investigation.

• Alendronate (Fosamax) and risedronate (Actonel) are the standard oral bisphosphonates. Studies on both these agents are very favorable and report a reduction in spinal and hip fracture in people with osteoporosis. They also prevent osteoporosis in people taking corticosteroids. Both are taken orally. Both can be taken daily and alendronate is now available as a weekly dose. (In fact, a 2001 study found that a the high weekly dose appears to have the same effects on bones as a daily dose.)
• An older oral bisphosphonate, etidronate (Didronel) can prevent early bone loss in menopausal women, help prevent fractures, and protect against bone loss in patients receiving high doses of corticosteroids. Some studies have not found it as effective as alendronate, however.
• Injected bisphosphonates are pamidronate (Aredia), zoledronic acid (Zometa), and ibandronate. These are very powerful agents, which are used to treat cancer patients. Because injections do not cause gastrointestinal side effects these agents are also being studied for postmenopausal women. In such cases, it may be possible to administer injections very infrequently. For example some studies suggest that zoledronic may need to be injected only once a year to improve bone density.
• Investigative bisphosphonates include clodronate and tiludronate. A 2001 study of clodronate reported that it prevented bone loss in patients with osteoporosis and helped prevent fractures.

Candidates. National Osteoporosis Foundations guidelines recommend that the following people should take or consider bisphosphonates:

• Women with a below normal bone density of 2.5 SD or greater and who have no history of fractures should take bisphosphonates.
• Women with below-normal bone density 1 SD or more and have a history of fractures should consider bisphosphonates.

Alendronate has also now been approved for men with osteoporosis. Both alendronate and risedronate are approved for both men and women who take corticosteroids.

Side Effects. The most distressing side effects are gastrointestinal problems, particularly stomach cramps and heartburn, which are very common, occurring in nearly half of patients. Patients should strictly adhere to instructions for taking the drug (although gastrointestinal problems may still occur).

• It is generally recommended that alendronate and risedronate be taken on an empty stomach in the morning with 6 to 8 ounces of water (not juice or carbonated or mineral water).
• The patient should remain upright and not eat for 30 minutes after taking the pill.
• Anyone taking the drug that develops chest pain, heartburn, or difficulty swallowing should stop taking the drug and see the physician. (It should be noted, however, that patients who stop taking the drug because of GI symptoms may be able to safely resume taking a bisphosphonate.)

Long-Term Risk for Ulcers. Evidence to date suggests that agents do not harm the upper GI tract (the esophagus and throat). Of concern, however, are studies reporting a higher risk for long-term injury and ulcers in the stomach and small intestine. Some of these cases may be due to osteoporosis and other factors that also put women at risk for ulcers and bleeding.

Click the icon to see an image of an ulcer.

One 2002 study, however, reported a significantly higher risk for ulcers (38%) in people who regularly took both Fosamax and naproxen compared to either drug alone. (The risk for ulcers was 8% with Fosamax alone and 12% with naproxen alone.) Naproxen (e.g., Aleve) is one of the NSAIDs, which are common pain relievers used for many conditions. Others include aspirin and ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen, ketoprofen (Actron, Orudis KT). Long-term use of NSAIDs alone is known to increase the risk of ulcers, so both agents may have a double effect on the stomach lining. It is not known yet if the risks for these adverse actions are as high with other combinations. For example, ibuprofen may have a lower risk for ulcers than naproxen, and Actonel may have fewer adverse effects on the stomach than Fosamax. Because so many older people take NSAIDs regularly clarifying these effects is very important.

Other Adverse Effects. Risedronate was associated with higher risk for lung cancer in one study, although not in others. (This association has not been found with other bisphosphonates.) More research needed.

Hormone Replacement Therapy

Based on early studies, many physicians used to believe that HRT might be beneficial for reducing the risk of heart disease and bone fractures caused by osteoporosis (thinning of the bones) in addition to treating menopausal symptoms. The results of a new study, called the Women's Health Initiative (WHI), has led physicians to revise their recommendations regarding HRT.

The WHI, started in 1993, has 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 July 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.

In March 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 other randomized clinical trials have linked HRT to an increased risk of heart attack and cognitive decline while conferring some protection against osteoporosis and colon cancer.

It should be noted that overall, these risks are still quite small. While the WHI study suggests that HRT should not be prescribed for prevention of chronic diseases, many physicians 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.

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

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

Both ERT and HRT 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 a topical estrogen gel which is applied to the arm.

Menopausal Symptoms and HRT. At this point 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.

Even short-term use of HRT poses some risk for blood clots and adverse heart events in some women. Furthermore, according to studies in 2002 and 2003, other than relieving hot flashes and other symptoms, taking HRT does not improve quality of life. In fact, in one study women who did not have hot flashes and took HRT generally had a worse quality of life, including fatigue and decline in physical functioning.

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 also be useful for some women at risk for osteoporosis, although other agents, such as bisphosphonates, should be considered first. It increases bone density and also appears to improve balance and protects against falling. Of note, although studies report reductions in fractures, it is unclear whether the reductions are significant. In any case, women who stop taking HRT begin to lose bone density, and after five years all protection is lost. It appears that estrogen must be taken life long for maximum protection against osteoporosis, which then increases the risk for adverse health effects. A 2002 study suggested that low doses may still be bone protective, and might also reduce health risks associated with HRT.

Other Possible Benefits of HRT

• Diabetes. Studies report that HRT may protect against diabetes, including in women with heart disease. Because of the risks with HRT, however, such findings do not indicate that HRT should be recommended for this purpose.
• Colon Cancer. Hormone replacement therapy, with or without progesterone, is associated with a reduced risk of colon cancer. Older women who are at risk for colon cancer might discuss hormone replacement therapy with their physicians if they have no strong risk factors for the adverse effects of HRT.

Click the icon to see an image of colon cancer.

Adverse Effects of HRT.

• Heart Disease. In spite of estrogen's benefits on cholesterol levels and other factors that effect the heart, the most recent 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. HRT, then, is no longer recommended for preventing either first or recurrent heart attacks.
• 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). 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, including a major 2003 analysis, have found no differences in mental performance and no protection from Alzheimer's disease in women taking HRT compared to non-users. In fact, in an important 2003 study, women who took combined HRT experienced a higher risk of mental decline.
• 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 growth of breast tissue 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 hormone replacement therapy (HRT), particularly with agents that contain both estrogen and progestin. Prolonged use increases the risk. A major study on HRT was stopped because of a slightly higher risk for breast cancer, although it should be noted the overall risk is still quite small. There was no effect, on mortality rates from breast cancer in HRT users. There has been some evidence suggesting that breast cancer in HRT users may have a more favorable outlook, including a lower recurrence rate than nonusers, but not all studies report such findings. HRT-related breast cancer may tend to develop in the lobes of the breast, where it is very slow-growing but more difficult to diagnose. Breast tissue density in any case increases with HRT, making mammograms more difficult to read.
• 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. (It should be noted that ovarian cancer is very uncommon in any case, 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 in HRT users.

Other Prescription Agents Used For Osteoporosis

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. It may be effective for spinal protection (but not hip) in both men and women. 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 low and intermittent doses of this hormone actually stimulates bone production. Unlike most treatments for osteoporosis, including bisphosphonates, the benefits may persist even after the injections have been stopped. Teriparatide (Forteo), an agent made from selected amino acids found in parathyroid hormone, has now been approved for treatment of osteoporosis in postmenopausal women. Studies suggest it significantly lowers the risk of fracture and increases bone mineral density. In one small study, parathyroid significantly reduced spinal fractures compared to hormone replacement therapy.

Prescription Agents Used for Menopausal Symptoms

Oral Contraceptives. Oral contraceptives (OCs) contain both estrogen and progestins. They generally use more potent forms of estrogen than those used for HRT and had not been thought suitable for replacement therapy. However, during the months before menopause, when periods may be irregular but contraception is still needed, low-dose forms of OCs may reduce the risk for bone loss and alleviate early menopausal symptoms, such as hot flashes. Like HRT they may protect bones in women approaching menopause (although they may have adverse effects on bones in young women.) Unlike HRT, they also protect against ovarian and endometrial cancers and do not appear to increase the risk for breast cancer. (Most studies on OCs, however, have been conducted with young women. The risks for women reaching menopause are not yet clear).

Antidepressants. The antidepressants known as selective serotonin-reuptake inhibitors (SSRIs) may be used for managing mood changes and hot flashes. They include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil, Asimia).

Testosterone. Some doctors are now prescribing combinations of estrogen and small amounts of the male hormone, testosterone. Estratest, for example, adds small doses of testosterone to estrogen therapy and appears to increase bone mass, improve sexual drive (when taken in higher doses), and improve mental alertness. A testosterone patch is also showing some promise in improve sexual function and well-being. 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 adverse effects are unknown.

Bellergal. Bellergal is the only non-hormonal drug specifically approved for hot flashes and other menopausal symptoms. This drug contains phenobarbital and belladonna and can be addictive. It relieves symptoms about half the time. It is not recommended in most cases.

Gabapentin. Several small studies suggest that gabapentin (Neurontin, a drug used for many neurologic conditions) may alleviate hot flashes. More research is needed. The drug is expensive and may cause sleepiness, dizziness, and clumsiness.