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"If only there were a pill."
Every man would like an easy way to stay healthy. Good nutrition and regular exercise are the keys for preventing illness, but diets take discipline and exercise takes time. Is there a shortcut? Can a few pills do the trick? Can "all-natural" supplements replace the physical activity and healthful eating that should be part of human nature?
If you look for the answer on the Internet or listen for it on TV or radio, you are likely to come away with a resounding "yes." That's mostly because vitamins, herbs, and other supplements are not subject to the jurisdiction of the Food and Drug Administration. Congress took care of that in 1994, when it passed the Dietary Supplement Health and Education Act. As a result, the supplement industry can tout its products without having to substantiate their claims for efficacy and safety. With billions of dollars at stake, the hype is relentless. In all, more than 50 percent of all Americans take supplements, spending upwards of $4 billion a year to buy health in a bottle.
Most doctors have been skeptical of supplements, pointing out correctly that anecdotes and testimonials can never be relied on in place of sound scientific studies. In the past few years, though, good studies have started to appear. While few herbs have been scrutinized, research by the Physicians' Health Study, the Health Professionals Study, and other investigations suggests that some supplements may be helpful while others are wasteful or even harmful. Surprisingly, perhaps, one of the most promising of all is not a vitamin or an herb, but an inexpensive, old-fashioned, medicine chest standby: aspirin.
Its name is more than a century old, but its parent compound has been in use for thousands of years. The ancient Assyrians, Egyptians, and Greeks all used willow leaves to treat inflammation, fever, and pain. The practice was popularized in England by Reverend Edward Stone in 1763. The active ingredient was purified from willow bark in Germany sixty-five years later. At the tail end of the nineteenth century, scientists at the Bayer Company succeeded in producing the modern derivative, acetylsalicylic acid, or aspirin. The very same drug has been used for fever and pain ever since. In the past thirty years, it has gained new importance in the management of heart disease and stroke, and current studies suggest it may someday assume a role in preventing colon cancer and possibly even Alzheimer's disease. And just as aspirin is finding new uses, scientists are finding out exactly how it works. It is important research that is likely to result in a new generation of even better drugs. But even in the dawning era of "super-aspirins," the original drug is certain to retain much of its value.
How It Works
Aspirin does its job by inhibiting the body's production of prostaglandins. Although you may never have heard of them, prostaglandins have a wide-ranging impact on human health. For example, they keep the stomach lining healthy, they regulate blood flow to the kidneys, and they enable platelets to trigger blood clotting. But prostaglandins also contribute to disease; in the brain they cause fever, and in joints and other tissues they can produce inflammation and pain.
Aspirin is not the only drug that inhibits prostaglandins. In fact all the nonsteroidal antiinflammatory drugs (NSAIDs) act in similar fashion (see Table 6.1, page 168). But although acetaminophen (Tylenol and other brands) fights fever and pain as well as aspirin, it does not inhibit prostaglandins. As a result, it does not share either the antiinflammatory benefits or the major side effects of aspirin and other NSAIDs.
Aspirin and Atherosclerosis
Aspirin does not prevent or even minimize atherosclerosis, but it can help prevent heart attacks and some strokes. It sounds like a paradox, but it is not. Aspirin cannot prevent cholesterol-laden plaques from building up in the wall of an artery, though it may be able to reduce the inflammation that perpetuates the damage (see Chapter Three and Figure 3.1). But while plaques narrow arteries, rarely do they produce the complete blockages that cause heart attacks. Instead, the culprit is a blood clot or thrombus that forms on the surface of a ruptured plaque. The clot completes the blockage, and aspirin exerts its protective effect by inhibiting clot formation.
Clots are triggered by platelets, fragmentary blood cells that are produced in the bone marrow, and then pour into the bloodstream. A man's blood contains a total of 100 million platelets, but because each platelet only lasts about ten days, the marrow must produce them continuously at a prodigious rate. Aspirin does not reduce the number of platelets in the blood, but it does inhibit their ability to trigger clots.
Platelets are extremely sensitive to aspirin. In some studies, doses as low as 10-30 milligrams can inhibit all the platelets in a man's body. Once platelets are inhibited by aspirin, they stay inhibited, but since new platelets are entering the blood continuously, the aspirin dose must be repeated every twenty-four to forty-eight hours to keep the majority of platelets under control.
Primary Prevention of Heart Attacks
You would probably call it staying healthy, but doctors call it primary prevention. By either name, it means heading off a problem before it makes its first appearance. Can aspirin prevent a first heart attack in men without diagnosed heart disease?
This is the question that the Physicians' Health Study set out to answer in 1982. A total of 22,071 male physicians volunteered to be subjects in a randomized clinical trial of low-dose aspirin. Half the men were assigned to take 325 milligrams of aspirin every other day, while the others each were given an identical-appearing placebo tablet every other day. To eliminate bias, the assignments were made randomly and neither the subjects nor the researchers knew which men were taking aspirin and which the placebo.
The researchers had planned to continue the trial until 1990, but it was terminated three years ahead of schedule. That was because an independent Data Monitoring Board that was tracking the results declared it would be unethical to continue the study since a clear winner was already evident. The winner was aspirin.
In the Physicians' Health Study, the men who took aspirin had a 44 percent reduction in the risk of suffering a heart attack. Benefit did not depend on a man's family history of heart disease or on his cholesterol, blood pressure, blood sugar, body fat, amount of exercise, or his drinking or smoking habits. But one risk factor did predict benefit: age. Aspirin was highly effective in men older than fifty, but not in younger individuals.
The results of the Physicians' Health Study were published in the same year as the report of the British Doctors Trial, which found no benefit from aspirin. Does that mean men should take aspirin in America but not in Europe? Not at all. The British trial was much smaller than the U.S. study, involving just 5,139 men. It was also less carefully controlled. But the biggest difference was in the dose of aspirin; the British doctors took 500 milligrams every day, the Americans just 325 milligrams every other day.
When you have a headache or a fever, you are likely to take two 325 milligram aspirin tablets every four to six hours. Even the British doctors' dose is tiny in comparison, but it may still be too high to produce maximum protection against heart attacks. That is because tiny doses of aspirin will inhibit only thromboxane A2, the enzyme in platelets that triggers the clotting process, but higher doses can also inhibit prostacyclin, an enzyme in blood vessels that reduces clotting. In theory, at least, low doses of aspirin will reduce clot formation, but even slightly higher doses might lessen that benefit. Two 1998 studies found that 75 milligrams of aspirin a day can reduce the risk of a first heart attack by about one-third, and a 2001 investigation found that 100 milligrams a day reduced the risk of cardiovascular death by 44 percent, but none of these reports investigated varying amounts of aspirin. However, a 1999 study from six European countries compared four aspirin doses and found that low amounts (81 or 325 milligrams a day) were actually better than higher doses (650 or 1,300 milligrams a day) in preventing strokes.
When it comes to aspirin for prevention, less is more.
Although the Physicians' Health Study demonstrated that low-dose aspirin could help prevent heart attacks in healthy men fifty or older, its 1989 report did not link aspirin use with a reduction in overall cardiovascular deaths. The aspirin trial was terminated early, and its five-year span may have been too short to discern an effect on mortality. But even after the randomized clinical trial was terminated, 11,010 of the subjects continued to take the drug on at least 180 days a year, while 3,849 took little or no aspirin. In 2000, the study reported that over a seven-year period, a low-dose aspirin was associated with a 35 percent reduction in cardiovascular deaths and a 36 percent drop in total mortality.
The Physicians' Health Study trial has provided additional information about aspirin's effect on the heart. The drug seems most effective in the early morning hours, when platelets are particularly likely to stick together and produce clots. It is a good thing, since that is when heart attacks are most likely to occur. Aspirin begins working rapidly and it remains effective as long as it is being taken. That is because the very first dose will inhibit all the platelets in a man's blood, but the body does not build up resistance to the drug. Aspirin was effective in preventing heart attacks in men who had angina, but it did not prevent healthy men from developing angina. That's because angina is caused by plaques that produce partial blockages, but heart attacks are the result of clots that form on plaques.
Secondary Prevention of Heart Attacks
The Physicians' Health Study was the first to show aspirin can protect healthy men older than fifty against heart attacks, but it was not the first to show that aspirin can help the heart. In fact, dozens of studies dating back to 1971 have demonstrated that aspirin has an important role in secondary prevention, in preventing second or third heart attacks in patients who have survived a first attack. In all, aspirin reduced the risk of recurrent heart attacks by about 25 percent. It only takes low doses of aspirin, between 75 and 325 milligrams a day, to produce this major benefit. At present, up to 25 percent of American heart attack survivors fail to take aspirin. It is a shame, since if all the heart attack patients who could take aspirin did so, it could prevent another 20,000 deaths annually.
Other Vascular Diseases
Atherosclerosis can strike any artery in the body; in addition to the heart, its most important targets are arteries in the legs and brain.
The Physicians' Health Study found that low-dose aspirin might protect the legs against severe blockages of peripheral artery disease. During an observation period that averaged about five years, men who took 325 milligrams of aspirin every other day were 46 percent less likely to require surgery for leg artery blockages than men who took placebos.
The issue of stroke is more complex because there are two types of strokes (see Chapter Three): hemorrhagic strokes occur when an artery in the brain ruptures, releasing blood into the tissue, but ischemic strokes result when clots block arteries in the brain. The Physicians' Health Study found that low-dose aspirin produces a slight increase in hemorrhagic strokes, but the heightened risk was too small to be statistically significant; other studies have reported similar results. At the same time, though, aspirin can help prevent ischemic strokes, which are four times more common than hemorrhagic strokes. In fact, two 1997 studies of more than 40,000 stroke patients found that low-dose aspirin (100 or 300 milligrams a day) produced a small but significant benefit, both by improving recovery and reducing the risk of a second stroke. More recently, a 1999 meta-analysis of eleven randomized, placebo-controlled trials found that low-dose aspirin reduced the risk of both types of stroke, combined, by 15 percent. But because high blood pressure increases the risk of hemorrhagic stroke, men with hypertension should not use low-dose aspirin until their blood pressures are brought under control (see Chapter Three).
Other Possible Benefits
Although the Physicians' Health Study was most interested in aspirin's effect on atherosclerosis, it also investigated other conditions. For example, it found that low-dose aspirin reduced the occurrence of migraine headaches by 20 percent. It also found a slight decrease in cataracts, but the difference was not statistically significant, and other research has failed to demonstrate protection against cataracts.
An area of much greater importance is the possibility that aspirin may reduce the risk of colon cancer. It is an unresolved question, and it is one of the few areas of disagreement among the Harvard men's health studies. The Physicians' Health Study found no reduction in colon cancer among the men who took 325 milligrams of aspirin every other day. In contrast, the Health Professionals Study found that men who used aspirin at least twice a week were 32 percent less likely to develop colon cancer than men who took it less often.
Although the issue is far from resolved, other research suggests that aspirin may help. In laboratory experiments, aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) can influence apoptosis, programmed cell death that prevents the unchecked growth of cancer cells (see Chapter Three). In rodents exposed to cancer-causing chemicals, NSAIDs inhibit the development of tumors in the colon. In animals and humans with hereditary polyps, NSAIDs can reverse the formation of the benign polyps from which colon cancers develop. In ten of twelve observational studies in humans, aspirin or other NSAIDs seemed protective. For example, in a 1991 American Cancer Society study of 662,424 people, aspirin use was associated with a 40 percent lower risk of dying from colon cancer over a six-year period. In all, the majority of studies report that NSAIDs use is associated with a 40 to 50 percent reduction in the risk of colon cancer.
The effects of NSAIDs on cognitive function are also intriguing. A sixteen-year study of 1,686 people in Baltimore linked the use of various NSAIDs to a 50 percent reduction in Alzheimer's disease. Although various NSAIDs appeared effective, aspirin itself was not protective. Other research, also preliminary, suggests that aspirin may reduce the risk of another type of mental decline, multi-infarct dementia, perhaps by preventing "mini strokes" (see Chapter Eight).
More research is needed to learn if aspirin can reduce a man's risk of colon cancer or dementia. At present, neither possibility is strong enough to serve as the sole reason to take aspirin. But since low-dose aspirin has a proven role in preventing heart attacks and some strokes, at least in men over fifty and in patients of any age who have had cardiovascular events, another reason is not really necessary.
Although you can buy it in convenience stores and vending machines, aspirin is a medication -- and a powerful one, at that. Like all medications, it can have side effects.
Bleeding is the most common adverse effect of aspirin and other NSAIDs. Even low-dose aspirin can prolong the oozing from a shaving nick or turn a small black and blue into a sizable bruise. Because aspirin inhibits platelets, it increases the risk of bleeding after injury, which is why no one should take NSAIDs within seven to ten days of elective surgery. More worrisome is stomach irritation and intestinal bleeding. In fact, about 41,000 Americans are hospitalized each year because of NSAID-induced intestinal bleeding. Other side effects can include ringing in the ears and elevated blood pressure, which is a particular concern for elderly patients or those with kidney disease. NSAIDs can cause temporary kidney dysfunction, especially in the elderly, and toxic doses of acetaminophen (Tylenol and other brands) and NSAIDs may produce permanent damage. In 2001, however, the Physicians Health Study found no evidence linking kidney disease to acetaminophen and NSAID use, even in men who had taken more than 2,500 pills during fourteen years of observation.
All of these aspirin side effects are dose-related; that is, they are much more common with higher doses than with the low dose used for prevention. In the Physicians' Health Study, aspirin was quite safe, though it did produce an increased risk of bleeding, which was usually minor. Still, men with histories of bleeding disorders, ulcers, hypertension, or kidney disease should not use aspirin without a doctor's okay, and the occasional man who is allergic to aspirin should not take it at all. Patients who take the anticoagulant warfarin (Coumadin) should not use aspirin or other NSAIDs unless they are specifically instructed to do so by their physicians; even then, close monitoring is mandatory.
Americans consume some 385 tons of aspirin and spend about $18 billion on NSAIDs every year. Table 6.1 lists some of the many brands of NSAIDs.
Table 6.1: Selected Nonsteroidal Antiinflammatory Drugs
Generic Name: Brand Name
Diclofinac: Voltaren, Cataflam
Ibuprofen: Advil, Motrin, and others
Ketoprofen: Orudis, Oruvail
Naproxen: Aleve, Anaprox, Naprelan, Naprosyn
All the NSAIDs inhibit prostaglandins, but they do not act on prostaglandins themselves. Instead, they inhibit cyclo-oxygenase (COX), the enzyme that generates prostaglandins. New research shows that there are actually two distinct forms of cyclo-oxygenase, COX-1, and COX-2. COX-1 is responsible for most of the "good" prostaglandins in the stomach and kidneys, while COX-2 is behind the "bad" prostaglandins that trigger inflammation, fever, and pain.
Aspirin and other NSAIDs produce many of their therapeutic effects by inhibiting COX-2, but because they also inhibit COX-1 they have unwanted side effects. New "super aspirin" including celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra) inhibit COX-2 but not COX-1. As a result, they can fight pain, inflammation, and fever, with a lower risk of stomach irritation and bleeding. Unfortunately, however, new research shows that the COX-2 inhibitors are far from perfect. They can trigger high blood pressure and kidney dysfunction, particularly in older people. The COX-2 inhibitors are also much more expensive than aspirin and most other NSAIDs, and because they are new, they may turn out to have additional side effects.
In terms of prevention, the COX-2 inhibitors may share aspirin's potential for inhibiting colon cancer, but they do not share low-dose aspirin's role in preventing heart attacks and strokes. To do that, a medication must block COX-1 -- or inhibit platelets in another way. Several drugs that inhibit platelets have been licensed for clinical use in the United States. Dipyridamole has long been available alone (Persantine), but is finding a new role in combination with aspirin (Aggrenox). For several years, cardiologists routinely prescribed ticlopidine (Ticlid) to prevent clots from reblocking coronary arteries newly opened by balloon angioplasty; it is effective but expensive. Although it spares the stomach, it has potentially serious side effects of its own, which is why it has been supplanted by a newer medication, cloidoquel (Plavix), which is safer but even more costly. In a 1996 study, cloidoquel proved slightly more effective than aspirin preventing cardiovascular events in 19,185 patients with atherosclerosis. Even more recently, the FDA approved turbofan (Aggrastat) and ebtifibatide (Intergrilin), injectable antiplatelet drugs modeled after viper venom, for early treatment of heart attacks. Attempts to develop oral forms of these drugs are underway, but have not yet been successful.
Is Low-Dose Aspirin Right For You?
If you have had angina, a heart attack, a transient ischemic attack, or an ischemic stroke (see Chapter Three), you should be taking low-dose aspirin. Unless, of course, you have a specific reason to stay away from the drug.
If you are a healthy man older than fifty, you may also benefit from low-dose aspirin. The presence of cardiac risk factors (see Chapter Three) would tip the scales in favor of aspirin, but a history of bleeding, ulcers, or other aspirin-related problems would argue against routine aspirin use.
If you decide to take aspirin, you will have to pick a dose and a preparation. Low doses are best, but regimens of 81 milligrams or 160 milligrams a day or 325 milligrams a day or every other day are all reasonable. Many doctors recommend enteric-coated preparations to reduce the risk of stomach irritation, but it is not certain that coated or buffered formulations are really safer than plain aspirin. In any case, be alert for side effects, such as stomach irritation or bleeding, no matter which tablet you choose.
What if you develop a fever or pain while you are on preventive doses of aspirin? Since low doses are best, the logical step would be to use acetaminophen (Tylenol and other brands), which does not affect platelets at all. A COX-2 inhibitor would be another, more costly, prescription alternative. Remember, though, to continue your low-dose aspirin for prevention while you are taking acetaminophen or a COX-2 inhibitor for therapy. But if you need an NSAID or high-dose aspirin to treat arthritis or other problems, go ahead and use it while you have to, then get back to low-dose aspirin for prevention.
Aspirin is not a panacea, but low doses can substantially reduce the risk of heart attack and stroke. If aspirin is right for you, take a tablet every day or two, but call your doctor in the morning if you suspect side effects. Do not pin all your hopes on aspirin alone; instead, use it in conjunction with diet and exercise to keep your heart healthy. And read on to learn about other supplements that may help.
The only way scientists can be sure if a supplement is beneficial is to conduct a randomized clinical trial. It is the way low-dose aspirin proved its worth, and the way beta-carotene and vitamin E lost their appeal (see Antioxidants, page 172). Multivitamins have not yet been subjected to this stern test, but even though proof of efficacy is lacking, many doctors are starting to recommend a daily multivitamin to nearly all their patients. I think it is the right thing to do. The cost is low, the risks are nil, and the potential benefits are substantial, depending largely on three B vitamins and vitamin D.
Folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin) may reduce the risk of heart attacks. These vitamins lower blood levels of homocysteine, a newly recognized cardiac risk factor (see Chapter Three). The evidence is best for folic acid and B6; in 1996, the Health Professionals Study found that a high intake of folic acid was associated with a 29 percent reduction in heart attacks, and that a high intake of B6 reduced risk by 23 percent. The Physicians' Health Study reported similar findings in the same year. And these benefits are not restricted to men. The Harvard-based Nurses' Health Study found women who had a high intake of folic acid and B6 had risks of heart attacks that were 31 and 33 percent lower, respectively, than women with low intakes; women who consumed healthy amounts of both vitamins enjoyed a 45 percent reduction in risk. More good news: it does not take megadoses of vitamins to produce these gains. In fact, just 400 micrograms of folic acid and 3 milligrams of B6 seem optimal. Both vitamins are found in leafy green vegetables and other foods, and folic acid is added to fortified breakfast cereals; still, many Americans do not get all they need (see Chapter Four).
Folic acid may also reduce the risk of colon cancer. In 1993, the Health Professionals Study and the Nurses' Health Study issued a combined report demonstrating that in both men and women a high intake of folic acid appeared to reduce the risk of the benign intestinal polyps from which cancers arise. In 1995, the Health Professionals Study found that a high intake of folic acid reduced the risk of colon cancer in men who drank alcohol, and in 1998, the Nurses' Health Study found that long-term use of folic-acid-containing multivitamins was associated with a substantial reduction in colon cancer.
Vitamin B12 is found naturally only in animal products, but is added to fortified cereals. Most American diets contain more than the 2.4 micrograms recommended each day, but strict vegetarian diets may provide less. Up to 30 percent of people over fifty do not absorb B12 well because they produce abnormally small amounts of stomach acid. A multivitamin can help by providing B12 in crystalline form, which is easier to absorb even without stomach acid.
The other important ingredient in a multivitamin is vitamin D (calciferol), which is essential for strong bones. It is hard to get enough vitamin D from your diet, and people who wisely avoid ultraviolet exposure in sunlight are often vitamin D-deficient (see Chapter Four).
Although multivitamins may be very beneficial, the gains depend on long-term use to reduce the risk of disease. If the Physicians' Health Study is right, you may even reduce your risk of cataracts as well as heart disease and colon cancer. In the short run, though, you cannot expect extra energy, improved sexuality, better sleep, less stress, or any of the other "benefits" hyped by the supplement industry. Look for a multivitamin that contains at least 400 micrograms of folic acid, 2-6 milligrams of B6, at least 2.4 micrograms of B12, and 400 International Units (IU) of vitamin D. Do not focus on other vitamins or minerals; most multivitamin tablets contain 50 to 100 percent of the recommended daily allowance of these chemicals, which is just fine (see Tables 4.8 and 4.9). Do not waste your money on designer vitamins that contain unnecessary herbs or other extras, megadoses, "all natural" preparations, or expensive brand names; generic multivitamins that contain the right amounts of the three B's and D will fill the bill. To assure quality, look for a formulation that meets the standards of the United States Pharmacopeia, a private rating organization; select a product that is fully labeled as to content, dosage, and expiration date. And remember that food is the best source of vitamins, minerals, and other nutrients. In particular, vegetables, fruits, and whole grain products supply dietary fiber and many other important nutrients as well as vitamins.
Just a few short years ago, multivitamins were in eclipse and antioxidant vitamins were the rage. New research on B vitamins, homocysteine, and vitamin D has put the spotlight on multivitamins, while studies of beta-carotene and vitamin E have dampened the enthusiasm for antioxidants.
What are Antioxidants?
Antioxidants protect the body against free radicals -- not the high-spirited youths of the Woodstock generation, but the high-energy molecules that are generated by the body's metabolism when it burns carbohydrates for energy. Free radicals are molecules that have extra, unpaired electrons; as a result, they are highly unstable. Oxygen free radicals are the most potent. In some circumstances, oxygen free radicals can be a boon to health; when they meet up with bacteria that have invaded the body, for example, they can use their extra energy to kill the microbes. But in other circumstances, oxygen free radicals are a bane; when they encounter LDL cholesterol, they turn it into the oxidized LDL that causes the inflammatory damage of atherosclerosis, and when oxygen free radicals attack DNA, they can contribute to defects that lead to unregulated cell growth, cancer (see Chapter Three). The damage caused by oxygen free radicals may also contribute to cataracts, dementia and other neurologic disorders, arthritis, and even the aging process itself.
The body produces oxygen free radicals continuously, but it also has an elaborate series of mechanisms to keep them in check. The food we eat can play a role in the struggle between oxygen free radicals and the antioxidants that neutralize them. Although oxygen free radicals are not present in natural foods, they can be produced when foods are processed or cooked. In particular, heating and frying can generate toxic oxidation products from polyunsaturated fatty acids. On the other side are the natural antioxidants in foods, including vitamin C, vitamin E, and vitamin A and its precursors in the carotenoid family.
Antioxidants in Foods
One of the most important and consistent findings in nutritional research is that people who eat the most fruits, vegetables, and whole grains have the lowest risk of heart attacks, strokes, cancer, and premature death. It is tempting to think that the vitamins in these foods play an important role in protection. Indeed, several studies have reported that people with low blood or tissue levels of vitamin C, vitamin E, or carotenoids have a high risk of atherosclerosis. But nutrition is very complex. The same foods that provide antioxidant vitamins are also high in B vitamins, dietary fiber, and various minerals. Any of these ingredients could be the protective element. Or, perhaps, a combination of ingredients is necessary for protection. To carry the argument one step further, the protection afforded by a healthy diet may depend as much on the absence of animal fat as on the presence of vitamin-rich vegetable foods.
The best advice, of course, is to eat lots of vegetables, fruits, and whole grains. The multivitamins that I also suggest provide modest amounts of antioxidant vitamins -- enough to prevent deficiency diseases, but much less than the amounts that some believe helpful for fighting heart disease and cancer. Should you take additional antioxidant supplements? In the case of beta-carotene the answer is no, in the case of vitamins E and C, maybe.
Carotenoids and Vitamin A
The carotenoids are a family of more than 600 chemicals. Found only in plants, they are converted to vitamin A by the tissues of herbivorous animals. First discovered in 1909, vitamin A is essential for night vision and for healthy skin, hair, bones, and teeth. In addition, vitamin A is an antioxidant. The average American gets about two-thirds of his vitamin A from meat and dairy products, the remainder from carotenoids in vegetables that are converted into vitamin A.
The U.S. Dietary Reference Intake for vitamin A is 5,000 International Units a day. Because vitamin A is fat soluble, it is stored away in the body's tissue. Over time, daily doses of 10,000 units or more can build up to toxic levels that can result in liver damage, brain swelling, eye and skin problems, and an increased fracture risk.
The carotenoids, in contrast, seem to be nontoxic, even in very large doses. For years, scientists thought that carotenoids were important only as precursors of vitamin A, but it is now clear that they have important activities of their own, including potent antioxidant properties. Carotenoids are present in deep green and yellow-orange fruits and vegetables such as carrots, pumpkin, squash, sweet potatoes, apricots, cantaloupe, spinach, broccoli, turnip greens, and Brussels sprouts. Beta-carotene is the best-known member of the family, but lycopene, which is found particularly in tomatoes, is an even more potent antioxidant.
There can be little doubt that eating carotenoid-rich foods is good for you (see Chapter Four). The Health Professionals Study provides an important example: A high intake of lycopene from tomatoes (especially cooked tomatoes) was linked to a 20 to 30 percent decrease in the risk of prostate cancer, and it reduced the risk of the most aggressive prostate cancers by 50 percent. But can a beta-carotene pill provide the same benefit as carrots, cantaloupe, and broccoli?
To find out, the Physicians' Health Study conducted a randomized clinical trial in concert with its low-dose aspirin study. Starting in 1982, 11,036 men between the ages of forty and eighty-four took 50 milligrams of beta-carotene every other day, while 11,035 took a placebo. The men were randomly assigned to take the vitamin or the placebo, and neither the subjects nor the researchers knew who was taking beta-carotene and who was taking the inert tablet. When the study concluded in 1995, the scientists found no difference between the two groups, either in terms of heart disease, stroke, cancer, or overall mortality; in particular, the rate of lung cancer and prostate cancer was not influenced by beta-carotene. And in 1999, the Physicians' Health Study reported that the beta-carotene supplements had not reduced the risk of diabetes.
Dr. Charles Hennekens, who directed the study, termed it the greatest disappointment of his professional career, but he was not the only researcher disappointed by beta-carotene. Beta-carotene has been studied in four other randomized clinical trials. The Beta-carotene and Retinol Efficacy Trial (CARET) administered 30 milligrams of beta-carotene and 25,000 international units of vitamin A or a placebo to 18,314 men and women who were at high risk of lung cancer because of smoking or asbestos exposure. The trial began in 1985 and was scheduled to run until 1997, but it was terminated prematurely because a trend was emerging. Unfortunately, the trend was in the "wrong" direction: There were actually more cases of lung cancer and cardiovascular disease and more deaths in the vitamin-treated group. As in the Physicians' Health Study, beta-carotene supplements had no effect on prostate cancer.
The Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Trial compared a placebo with alpha-tocopherol (vitamin E, 50 milligrams) and beta-carotene (20 milligrams), either alone or in combination. The subjects were 29,133 Finnish male smokers. As in the CARET study, the men who took beta-carotene had an increased incidence of lung cancer and a slight increase in deaths from heart disease. Unlike the Physicians' Health Study and the CARET trial, however, the ATBC trial noted a slight increase in the risk of prostate cancer among the men who took beta-carotene. In contrast, vitamin E did appear to decrease the risk of prostate cancer (see vitamin E, below), but it did not affect the risk of lung cancer or cardiac deaths.
Another trial of beta-carotene was different in two respects. First, it did not test beta-carotene (15 milligrams) alone, but in a cocktail that also contained vitamin E (130 milligrams) and selenium (50 micrograms). Second, the subjects were not well-nourished Americans or Finns, but 29,584 poorly nourished residents of Linxian, China. In this population, the triple cocktail appeared to reduce the overall death rate, largely due to a decline in stomach cancer and other malignancies.
The final trial was much smaller, involving just 1,720 Americans, but it illustrates the dilemma of beta-carotene. When researchers measured beta-carotene blood levels before they administered the vitamin, they found that the people with the lowest blood levels had the highest risk of dying from cardiovascular disease and all other causes. But supplements of 50 milligrams of beta-carotene a day for more than four years did not change things, even for the people whose initial blood levels were low.
We do not yet know why beta-carotene supplements appear to increase the risk of lung cancer in smokers; part of the explanation may depend on the fact that smoking lowers vitamin C levels. Even though beta-carotene seems safe in nonsmokers, it is not beneficial.
It is an important message about beta-carotene and a cautionary tale for other supplements: Vitamin-rich foods are associated with better health but, in the case of beta-carotene at least, supplements are not.
Vitamin E is not a single compound but a family of chemicals called tocopherols. The most common member of the group is alpha-tocopherol, which is the form of vitamin E that is present in most supplements. Alpha-tocopherol was first discovered in 1922; despite our long familiarity with it, however, vitamin E is in many respects a mystery vitamin. Its precise function in the human metabolism is not known, and there is no clearly defined vitamin E deficiency disease. But it is clear that vitamin E is a potent antioxidant, and it appears to act as the first line of defense against oxygen free radicals. As a fat-soluble vitamin, in fact, vitamin E travels in the same package that carries LDL cholesterol, even entering the arterial wall with LDL. Vitamin E can also accumulate in the body's fat depots. There is concern that high doses might interfere with blood clotting or with the body's ability to fight infection, but actual toxic effects have not been documented.
For men, the Dietary Reference Intake of vitamin E is 15 milligrams, or about 22 International Units, a day. Vitamin E is present in many foods, including vegetable oils, wheat germ, nuts, butter, eggs, and margarine. In addition, most cereals are fortified with vitamin E. It's not hard to get the RDA of vitamin E from foods -- a tablespoon of canola oil, for example, has about 12 international units -- but it is very difficult to get the higher amounts that may help protect the heart without taking supplements.
In 1996, the Health Professionals Study provided some optimistic news about vitamin E; men who took at least 100 international units of vitamin E a day for two years or longer enjoyed a 37 percent lower risk of developing heart disease than men who did not take supplements. Similar results in women were reported by the Nurses' Health Study in the same year.
Although their findings were hopeful, these observational studies cannot establish a cause and effect relationship. Randomized clinical trials are the best way to do that, but for vitamin E and cardiovascular disease the latest evidence is discouraging. The ATBC trial found no benefit against heart disease in male smokers, but the dose of 50 milligrams, or about 75 international units, was low. However, a two-year Italian study of 11,324 heart attack survivors found that 300 milligrams of vitamin E did not protect against cardiac events. Similarly, the nineteen-nation HOPE trial of 9,541 patients failed to detect benefit from 400 international units of vitamin E over a four-and-a-half-year period. And in 2001, the Primary Prevention Project study of 4,495 people with cardiovascular risk factors found no benefit from 300 milligrams of vitamin E a day for nearly four years. Standing alone on the positive side of the ledger, the Cambridge Heart Antioxidant study (CHAOS) found that over a one-year period, a daily dose of 400 or 800 international units of vitamin E reduced the risk of heart attack in patients with known coronary artery disease. Even in this study, however, vitamin E did not reduce cardiovascular deaths.
Although scientists have been most interested in the possibility that vitamin E may reduce the risk of heart disease, they have evaluated other potential roles for the vitamin. The Health Professionals Study reported that vitamin E appeared to reduce a man's risk of bladder cancer, but it detected no protection against stroke. However, a small Rhode Island study of 100 patients with transient ischemic attacks ("mini-strokes") suggested that 400 international units of vitamin E could add to the protection afforded by aspirin. A 1994 study suggested that a very high dose of vitamin E, 2000 international units a day, might slow the progression of Alzheimer's disease, but there is no evidence that the vitamin will prevent healthy men from developing the disease. Although there is new evidence that a supplement containing zinc and multiple antioxidants can reduce the risk of visual loss due to macular degeneration, the Physicians' Health Study found no evidence of protection from vitamin E, vitamin C, or multivitamins.
Prostate cancer is a special concern for men, and here, too, vitamin E has had its ups and downs. The ATBC trial raised our hopes when it reported that supplements of vitamin E appeared to reduce the risk of dying from prostate cancer by 41 percent. But all 29,133 Finnish men in the trial were smokers. When the Health Professionals' Study evaluated the impact of vitamin E on prostate cancer, it found that apparent protection was confined to men who were smokers or recent quitters; nonsmokers did not benefit from vitamin E supplements.
The vitamin E story is complex, and its benefits for the prostate are far from certain. But even before the last chapter has been written, new research tells us that the situation is even more complex than it seemed.
The latest player is gamma-tocopherol, a form of vitamin E that is found in foods such as soybean and corn oil, but not in most supplements. A 2001 study of 10,456 residents of Maryland found that men with the highest blood levels of gamma-tocopherol were only one-fifth as likely to develop prostate cancer as men with the lowest levels. High levels of selenium and alpha-tocopherol also seemed to help, at least in men who also had high levels of gamma-tocopheral. And if this were not complex enough there is another wrinkle: vitamin E supplements that provide alpha-tocopherol (especially above 400 international units) may actually lower blood levels of gamma-tocopherol.
It will take time for scientists to sort this out. The Physicians' Health Study has begun a randomized clinical trial of vitamin E that may resolve the uncertainties. But until the results are available, soy is looking pretty good (see Chapter Twelve).
Vitamin C is one of the most popular supplements in America. Doctor Linus Pauling was responsible for much of its appeal; his stature as the winner of two Nobel Prizes -- one for Chemistry and one for Peace -- helped popularize his theory that megadoses of vitamin C prevent the common cold. Controlled clinical trials have disproved that theory, but vitamin C remains a best seller. Newer theories suggest that it may reduce the risk of heart disease and cancer, but the evidence is mixed at best.
Vitamin C (ascorbic acid) has an important role in the body's metabolism. It is a cofactor for at least eight enzymes involved in building proteins from amino acids and in the production of a stress hormone in the adrenaline family. Vitamin C is also an antioxidant. Research suggests that its main roles are to scavenge free radicals that have escaped vitamin E and beta-carotene, and to regenerate vitamin E. The Dietary Reference Intake for vitamin C is 90 milligrams a day. Vitamin C is found in many fruits and vegetables, including citrus fruits, potatoes, broccoli, melons, tomatoes, spinach, and cabbage; a cup of orange juice contains 120 milligrams. Dietary deficiencies of vitamin C cause scurvy, but that disease is now very rare in the United States.
Several studies suggest that people who eat large amounts of vitamin C-rich foods have a lower risk of heart disease and cancer. It is not clear, though, if the benefit depends on vitamin C itself or on other substances in fruits and vegetables. The Health Professionals Study found no evidence that a high intake of vitamin C reduces the risk of heart attack or stroke, and the Nurses' Health Study reported similar results. To date, no study has demonstrated benefit from vitamin C supplements. To clarify the issue, the Physicians' Health Study has embarked on a randomized clinical trial of vitamin C tablets in men.
Men should eat at least five servings of fruits and vegetables a day (see Chapter Four); meeting this goal will provide 200 to 300 milligrams of vitamin C a day. There is no evidence that additional doses are helpful, but men who wish to take more should not exceed 250 to 500 milligrams a day, since higher doses may be counterproductive.
Niacin (Vitamin B3)
Niacin is a vitamin that goes by several names: nicotinic acid, niacinamide, and vitamin B3. By any name, it is a water-soluble vitamin that has an important role in enabling the body to obtain energy from carbohydrates, fats, and proteins. People who don't get enough niacin develop pellegra, a deficiency disease characterized by diarrhea, fatigue, confusion, and a rash. Niacin deficiency is exceedingly rare in the developed world, since just 20 milligrams a day will maintain health. The vitamin is found in many foods, including legumes, peanuts, fish, poultry, meat, eggs, and products made from fortified grains.
Even though healthy men do not need extra niacin, it is present in multivitamins. However, niacin supplements are heavily promoted on their own to reduce cholesterol levels. They do work; niacin can lower LDL ("bad") cholesterol levels by 20 to 40 percent, making it as effective as many statin drugs. Niacin will also lower triglyceride levels by 40 to 60 percent, something most statins cannot do. Best of all, niacin is unrivaled in ability to boost HDL ("good") cholesterol levels, often by 10 to 30 percent.
An all-natural, inexpensive vitamin with wonderful effects on blood cholesterol levels -- it sounds too good to be true. It is true, but there is an important catch: To improve blood cholesterol levels, niacin must be consumed in amounts 25 to 150 times above the DRI, or 500 to 3,000 milligrams a day. In these doses, niacin can have major side effects, including liver inflammation, headaches, itching and flushing of the skin, gout, internal bleeding, high blood sugar levels, and sexual dysfunction.
All in all, niacin is a poster boy for the case against unregulated nutritional supplements. It actually is a nutrient, and it does work -- two things that many supplements do not have going for them. But preparations vary substantially in potency and purity, so a man cannot be sure what he is getting when he swallows a niacin tablet. And in the doses that work, niacin can have major side effects.
Do not take niacin on your own. But if you have a high LDL and a low HDL that does not respond to diet and exercise, ask your doctor to consider niacin among your medicinal options. If your doctor recommends niacin, use it carefully: Pick one preparation and stick with it; increase the dose gradually, listen to your body to detect problems, and have regular medical tests to detect side effects.
Although it is sold as a nonprescription supplement, in therapeutic doses niacin is actually a powerful drug. Treat it as such, using it only under your doctor's supervision.
Selenium is a trace element that is essential for health. Only small amounts are required; the DRI for men is just 55 micrograms. Selenium is provided by many foods, including tomatoes, shellfish, poultry, garlic, meat, and whole grains and vegetables grown in selenium-rich soils.
Scientists have been interested in selenium because it functions as an antioxidant. As a result, doctors have wondered if selenium might help prevent heart attacks or cancer. To date, the evidence is mixed.
In 1982, a Finnish study reported that people with low blood selenium levels had an increased risk for developing coronary artery disease, and a 1991 study of Finnish men linked low selenium levels to atherosclerosis of the carotid artery. In 1995, however, the Physicians' Health Study cast considerable doubt on the hypothesis that selenium protects the heart. In fact, in American men, high selenium levels were associated with a slight increase in heart attack risk.
To learn if selenium supplements might reduce the risk of recurrent skin cancer, a team of scientists headquartered in Arizona administered either 200 micrograms of selenium or a placebo to 1,312 volunteers with an average age of sixty-three; the participants took their tablets daily for an average of four-and-a-half years. When the study ended in 1996, the researchers were disappointed to learn that there was no difference in the occurrence of skin cancer between the two groups, but they were startled to find that there were about 50 percent fewer cancer deaths in the selenium group. Selenium was linked to a significant reduction in deaths from lung, colon, esophageal, and prostate cancer; protections appeared strongest for prostate cancer, with 63 percent fewer deaths in the men who took selenium. These results were greeted with great interest but also with caution; some doctors felt they were too good to be true, and most stressed the need for further research.
In 1998, the Health Professionals Study provided some of that additional research. Instead of administering supplements, the researchers evaluated the mineral intake by analyzing the selenium content of toenail clippings submitted by 33,737 men. The men who had the highest selenium levels were only about one-third as likely to develop advanced prostate cancer as the men with the lowest levels. The Harvard team calculated that a daily intake of 159 micrograms of selenium would achieve the protective levels.
Despite these two encouraging studies, it is too early to make a blanket recommendation for selenium. Still, until more data are available, a supplement of 200 micrograms a day would be a reasonable choice for men, particularly those with an increased prostrate cancer risk (see Chapters Three and Twelve). Remember, though, that excessive amounts of selenium can be toxic; hair loss and skin disorders begin to appear at levels above 400 micrograms a day.
Chromium is another trace metal that is important for carbohydrate metabolism; the precise daily requirement is not known, but the Food and Nutrition Board of the National Academy of Sciences suggests a daily intake of 35 micrograms a day. Dietary sources of chromium include brewer's yeast, peanuts, legumes, and whole grains as well as meat and cheese.
Do not believe most of what you hear about chromium. A compound called chromium picolinate is heavily promoted for weight loss, increased energy, and other "benefits." Unfortunately, there is no evidence to support any of these claims, and in test-tube experiments, large amounts of chromium picolinate may cause cell damage.
Although chromium does not live up to its hype, it may have one benefit that can help some men. Between 1968 and 1982, six independent trials suggested that chromium might raise HDL cholesterol levels, but these studies were small and flawed. In 1991, however, doctors in North Carolina tested an organic form of chromium against a placebo in sixty-three men with low HDL levels. Over a two-month period, the mineral produced a 16 percent rise in the average HDL levels without any apparent side effects. It is only one trial and only lasted two months. More research is needed to see if chromium can produce a sustained rise in HDLs. Until new information is available, men with low HDLs can consider trying the North Carolina regimen of a form of chromium called glucose tolerance factor (GTF) in a dose of 200 micrograms three times a day. Needless to say, though, no one should turn to GTF without first trying to raise his HDL through quitting smoking (Chapter Eight), exercise (Chapter Five), weight loss and diet (Chapter Four), and possibly low-dose alcohol (Chapter Seven).
If you do not believe that supplements are a big business, just stroll down the aisles of a few drug stores, supermarkets, or health food shops. The array of products is bewildering, the claims made for them no less overwhelming. Aside from the supplements we have discussed here and possibly calcium (see Chapter Four), there is no reason for healthy men to consider any of these products. A few may be useful for men with specific health problems, but because these products are unregulated, there is no assurance about efficacy or safety, potency or purity. Here is a quick run-down on some of the most popular supplements.
It is an herbal extract sold under many names for the treatment of prostate disorders. Studies in Europe suggest that it may alleviate symptoms of benign prostatic hyperplasia (BPH), but there is no evidence that it will prevent BPH, much less prostate cancer. Saw palmetto has no effect on sexual function. Despite scientific uncertainties, men with BPH who do not respond well to prescription medications might consider a trial of saw palmetto -- after checking with their doctors, of course (see Chapter Eleven).
Doctors first became aware of the potential benefits of fish oil in 1971, when Danish scientists reported that the Eskimos of Greenland had a very low rate of heart attacks despite eating large amounts of fat. They postulated that protection depended on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), two omega-3 fatty acids found in fish oil.
Over the past thirty years, researchers have accumulated a substantial body of evidence that eating fish is beneficial. In one study, people who consumed at least 8.75 ounces of fish a week enjoyed a 38 percent reduction in fatal heart attacks, and in another, heart attack survivors who ate fish twice a week were 29 percent less likely to suffer recurrent attacks than comparable patients who did not eat fish. Although not all studies agree that eating fish protects against heart attacks, fish consumption has been linked with a reduced risk of sudden death, hypertension, and stroke (see Chapter Four).
If eating fish is helpful, perhaps men should skip the shopping and cooking and take their fish oil straight up. Indeed, fish oil was a popular supplement in the 1980s, but it began to fade when studies reported little sustained benefit.
Two 1999 studies are reviving interest in fish oil supplements. Doctors in Germany administered capsules containing fish oil or vegetable oil to 223 heart patients. After two years, the people who took fish oil (6 grams a day for 3 months, then 3 grams a day) had fewer cardiac events and better angiograms than their peers, but the protection was modest. A much larger Italian study of 11,324 heart attack survivors was more positive, reporting that just 882 milligrams of EPA and DHA a day appeared to reduce the risk of cardiac events by 10 percent.
It is far too early to recommend fish oil supplements for everyone, or even for all cardiac patients. For now, eat your fish and stay tuned for the results of additional research.
Garlic (Allium satirum) traces its origins to central Asia. Although the plant grew wild for centuries, it now exists only as a cultivated crop. About 2 million tons are harvested annually. Most garlic is processed into a dry powder, but some medicinal preparations use oil that is extracted from the cloves. Garlic can also be aged and fermented to remove its odor. Garlic powder is considered the most medically active preparation, deodorized garlic, the least.
Of the nearly 100 chemicals in garlic, the most important appears to be allicin, a sulfur-containing amino acid. Allicin is not present in fresh garlic, but it is formed instantly from its parent chemical when cloves are crushed or cut. Scientists believe that allicin is responsible for the biologic activity of garlic; cooks know it is responsible for the characteristic odor that has earned the name "stinking rose." Most garlic powder preparations are standardized to contain a specified amount of allicin. Laboratory experiments have studied either whole garlic or purified extracts, but most clinical trials have used garlic powder.
Garlic is widely promoted to fight heart disease. Experiments in animals and test tubes suggest that garlic may help in several ways, by lowering cholesterol, reducing blood pressure, keeping arteries supple, and fighting clot formation. Experiments in test tubes and rats do not necessarily translate into benefits for humans. In the past ten years, however, there have been credible human studies of garlic and health, but the results are mixed.
The possibility that garlic could lower cholesterol in humans got a big boost in the early 1990s. First, studies in Germany found that a popular garlic powder (Kwai) could lower cholesterol levels by 12 percent. In 1993 researchers in New Orleans reported that tablets providing 900 milligrams of garlic powder a day could reduce LDL ("bad") cholesterol levels by 11 percent; garlic was particularly effective in people with high cholesterol levels. A 1994 British meta-analysis of sixteen trials also reached a favorable conclusion, predicting a 12 percent reduction in cholesterol.
Unfortunately, subsequent research has been less encouraging. Two groups of Australian researchers broke the bad news. A 1995 study of twenty-eight subjects and a 1996 investigation of 115 people with high cholesterol levels found no benefit from garlic, even though both used the same tablets that appeared effective in Germany. A 1996 American study that used a different preparation, aged garlic extract, was more optimistic, but it demonstrated a cholesterol reduction of just 6 percent. Even those results, though, look good in comparison to more recent research: A German study of garlic oil extract and Canadian and American studies of garlic powder have all reported no benefit.
Garlic is nearly as popular as a remedy for high blood pressure as it is for high cholesterol. As with cholesterol, there is a whiff of evidence that it may help. A British meta-analysis of eight trials of garlic powder reported a 7 millimeter drop in systolic blood pressure (the higher blood pressure number, measured while the heart is pumping blood into the arteries) and a 5 millimeter drop in diastolic blood pressure (the lower number, measured when the heart is refilling with blood between beats).
Investigations of garlic's effects on arteries themselves have received less publicity but may be more significant in the long run. A 1997 study from Germany evaluated the elasticity (flexibility) of the body's main artery, the aorta. Researchers compared 101 adults who had been using garlic powder for at least two years with an equal number who had not taken garlic. All the subjects were between fifty and eighty years of age and none were taking cardiovascular medications. Although blood vessels grew stiffer with age in both groups, ultrasound testing showed that the garlic users in all age groups had more flexible arteries.
Although the 1997 investigation of elasticity is interesting, it is not a randomized clinical trial. But in a 1999 study that evaluated the carotid (neck) and femoral (leg) arteries in 152 patients with atherosclerosis who were randomly assigned to receive garlic powder or a placebo over a two-year period, garlic appeared to slow the progression of cholesterol-laden plaques, which even regressed in some subjects.
The major side effect of garlic is obvious. In Shakespeare's A Midsummer Night's Dream, Bottom advised his fellow actors to "eat no onions nor garlic, for we are to utter sweet breath." In addition to bad breath, garlic can induce gastroesophageal reflux disease (GERD) and heartburn. Less common problems include flatulence and rashes. Because garlic may reduce blood clotting, people taking aspirin, warfarin (Coumadin), or other anticoagulants (blood thinners), should use garlic with care.
Is garlic right for you? That depends on your goals. If your aim is to make a great pasta sauce, the answer is yes. But if you are interested in garlic for health, the only realistic answer is maybe.
Garlic may help reduce cholesterol levels, lower blood pressure, and protect blood vessels, but the evidence of benefit is mixed, even contradictory. Preliminary studies hint that garlic may have a role in reducing the risk of gastrointestinal cancer, but this potential benefit is even more speculative. If you decide to give garlic a try, remember that tablets containing garlic powder have the best shot at helping. A reasonable dose is 300 milligrams of garlic powder three times a day. But, like all dietary supplements, garlic pills are not subject to FDA standards for purity or contents. You should pick a brand that promises to deliver 1 to 1.5 percent allicin, but there are no assurances that it will live up to that goal. Unfortunately, deodorized preparations are less likely to deliver the active chemical.
Above all, do not count on garlic. If you are attracted to the herb, and if you and your companions don't mind the odor, use garlic to supplement things of proven benefit. For cholesterol and blood pressure, regular exercise, weight control, tobacco avoidance, and a diet low in saturated fat, cholesterol, and salt but high in fruits, vegetables, and fiber is the way to start.
Glucosamine is a natural compound present in most human tissue, including joints, where it has an important role in the metabolism of various proteins in cartilage. Chondroitin is a larger substance composed of many glucosamine molecules linked to sugar molecules.
Best-selling books to the contrary, glucosamine-chondroitin sulfate is not an "arthritis cure." Several randomized clinical trials, though, do suggest that it may be mildly effective in relieving the pain of osteoarthritis, and a 2001 study suggested that it may actually slow the progression of joint damage. A recent meta-analysis of all the trials concluded that although these studies demonstrate benefits, most have technical flaws that prevent firm conclusions.
Glucosamine-chondroitin sulfate may be worth a try for men with arthritis pain that does not respond satisfactorily to standard therapies, including weight loss, exercise, joint protection, heat and cold applications, and pain relievers or anti-inflammatory medications. Patients with diabetes should be cautious, since glucosamine may increase blood-sugar levels. The supplement may interact with anticoagulants; the long-term safety and efficacy of glucosamine-chondroitin sulfate is not known.
St. John's Wort
Botanists know it as Hypericum perforathum, but it got its common name centuries ago because it is a plant ("wort" in old English) that produces its bright yellow flowers in June, around the time of John the Baptist's birthday. By any name, it has become a best-selling herbal remedy for depression, outselling Prozac by four to one in the United States.
St. John's wort is available in the United States without prescription. It is licensed for the treatment of depression, anxiety, and insomnia in Germany, and it has been widely used throughout Europe. A meta-analysis of twenty-three trials involving 1,757 patients with mild to moderate depression concluded that St. John's wort is as effective as tricyclic antidepressants. In most of these studies, however, the diagnosis of depression was not well established, the dosage of prescription antidepressants was low, and the observation periods were brief.
St. John's wort is less expensive than prescription antidepressants and it has fewer side effects, though a few patients have reported dry mouth, dizziness, constipation, and other mild disturbances. However, additional studies will be required to confirm its efficacy and to compare it with the newer prescription antidepressants.
The active ingredient in St. John's wort appears to be hypericin, a chemical that inhibits the uptake of serotonin and other neurotransmitters. As a result, it may not be safe to take St. John's wort along with prescription antidepressants. The dose of hypericin varies from brand to brand. The contents, potency, and purity of the preparations sold in America have not been evaluated by the FDA or any other reliable source.
Like many herbal medications, St. John's wort is heavily promoted. It may have some benefit, but it is not a cure-all for depression, and it should never be used as a substitute for standard therapy. More studies will be needed to evaluate its role.
Dating back 200 million years, gingko biloba, the maidenhair tree, is the oldest species of tree alive today. Extracts of gingko leaves have been used in Asia for centuries, and it is currently one of the most widely used medications in Germany. Gingko extract contains numerous chemicals; various flavonoids are among the most active ingredients. In animal and laboratory experiments, gingko extracts appear to increase blood flow, inhibit platelet-activating factor, and neutralize oxygen free radicals.
Gingko is principally promoted to improve memory and enhance the circulation. A highly-publicized 1997 American study of 203 individuals reported that a particular gingko extract, EGb761, was able to stabilize or improve cognitive performance and social function in patients with Alzheimer's disease or multi-infarct dementia, another common cause of mental deterioration in the elderly. However, the improvement occurred in only 27 percent of patients and was modest at that. Unfortunately, a 2000 study in 123 patients with dementia found no benefit from gingko, and there is no good evidence to support claims that gingko prevents mental deterioration or enhances cognitive function in healthy people (see Chapter Eight). European studies suggest that gingko may improve pain-free walking in patients with intermittent claudication caused by peripheral vascular disease (see Chapter Fourteen). Few side effects have been recorded.
Given the limited alternatives, it may be reasonable for caregivers to administer gingko to patients with cognitive impairment. It is also possible that people with intermittent claudication might experience improvement. The EGb761 formulation has been best studied; a common dose is 40 milligrams three times a day or 80 milligrams twice a day.
Despite the paucity of evidence that gingko can help healthy people, it has become the third best-selling herbal supplement in America, to the tune of $270 million a year.
Although many herbal medications trace their origins to Asia, echinacea is a native American, the purple cornflower. It is used in Germany to treat infections of the respiratory and urogenital tracts and to enhance wound healing. In the United States, where echinacea is the best-selling herbal medication, it is heavily promoted to prevent and treat colds. Studies of echinacea have recorded mixed results; most are methodically flawed. The most optimistic studies suggest that echinacea may shorten the duration of cold symptoms by about a third. Few side effects have been reported; despite this apparent safety, there seems little reason to recommend echinacea.
Extracts from the ginseng root have been used in Asia for more than 2,000 years. Today it is one of the most popular herbal products in the world. It is also one of the most expensive. Perhaps because this slow-growing perennial has a shape that reminds some observers of the human form, it is popularly known as the "man root" and is touted to enhance all parts of the body. In the United States, ginseng is touted as a general tonic to enhance energy, relieve stress, slow the aging process, improve sexual performance, and promote vitality.
Despite the popularity of ginseng, its chemical ingredients are poorly understood. Most products contain only 2 to 3 percent of the presumed active components know as ginsenosides. Human studies are scant, contradictory, and methodologically flawed. Few side effects have been reported; disappointment may be the most common.
Claims that zinc helps the prostate are unfounded, and claims that zinc lozenges can ease the symptoms of colds are based on contradictory data. Zinc is often recommended for macular degeneration, and a recent study shows that it appears to help, at least when it is combined with antioxidant vitamins.
Anecdotal evidence is cited to support occasional use of melatonin for jet lag or insomnia. Extravagant claims that melatonin helps fight aging, cancer, and other problems are unfounded. The long-term safety of melatonin is not known.
One of the twenty natural amino acids that the body uses to make proteins, creatine is present in many of the body's tissues. Creatine is particularly concentrated in muscle, where it has an important role in generating energy. But the body can produce 1 to 2 grams of creatine a day on its own, and the average diet will provide another gram or two, mostly from meat, fish, and milk.
Very high doses of creatine, 20 grams a day, about the amount contained in ten pounds of steak, can increase muscle performance, but only for very brief, high intensity, repetitive tasks such as weight lifting, and only to a modest degree, perhaps 4 percent. Away from the lab, field trials of creatine have found little or no benefit on actual athletic performance. Preliminary studies suggest that creatine may help certain patients with severe neuromuscular diseases. The long-term safety of creatine is not known. Sammy Sosa notwithstanding, creatine cannot be recommended as a supplement.
Since Mark McGwire revealed that he took andro during his epic seventy home run season, andro has become wildly popular as a performance-enhancing supplement. It is sold as a nutritional supplement, but it has no role in human nutrition. Instead it is an androgen, a male hormone (see Chapters One and Ten). Recent studies suggest that it does not enhance performance but may have serious side effects. Do not take it.
Like andro, dehydroepiandrosterone (DHEA) is not a nutrient but a steroid hormone. DHEA is produced in the adrenal gland; its function is a mystery, but it is converted into androgens and estrogens, male and female hormones.
Because DHEA levels are high in young adulthood but low in old age, it has been hyped relentlessly as an antiaging supplement that will burn away body fat, build muscle, enhance sexual performance, slow memory loss, boost the immune system, and fight heart disease and cancer, among other things. There is no evidence that it works, and some reasons to worry that long-term use could have serious side effects, including benign prostate hyperplasia and prostate cancer. Do not take it.
More to Avoid
Other supplements to avoid include yohimbine, sold for potency; lecithin, sold for cholesterol; coenzyme Q, sold for heart disease; and ephedrine, sold for weight reduction but often used for "herbal high." In fact, it is a good idea to stay away from any product that has not been evaluated by competent, unbiased medical scientists.
When it comes to supplements, the stakes are high, both in money and in health. It may be entirely reasonable for you to use a supplement, but before you do, consider these facts:
Medical science is finally starting to give supplements the study they need so badly. Along with other research, the Harvard men's health studies suggest that low-dose aspirin may have an important preventive role, at least for men over fifty and for everyone with atherosclerosis who can take aspirin. Because they provide folate and vitamins B6, B12, and D, multivitamins make sense for nearly everyone. However, vitamin E has been disappointing, vitamin C has not been proven helpful, and beta-carotene may do more harm than good. In contrast, selenium may prove beneficial. Men with low HDL cholesterol levels may benefit from chromium or niacin, but they should only be used as part of a comprehensive, medically supervised program. A few herbal products may merit consideration in special circumstances, but men should not rely on them as panaceas, and they must remember that there is no proof that unregulated products are safe or effective.
Caveat emptor, buyer beware!
Copyright © 2002 by the Presidents and Fellows of Harvard College
Prologue: The Time Has Come
PART I In Health and Sickness: The Unique Attributes of Men
One: What Makes a Man?
Two: Questions and Answers: The Harvard Men's Health Studies
Three: Perils and Problems: Three Leading Killers of American Men
PART II What Keeps Men Healthy?
Four: The Answers: Diet
Five: The Answers: Exercise
Six: The Answers: Aspirin and Other
Seven: An Answer for Some, a Peril for Others:
Eight: The Answers: Behavior Modification and
PART III The Maladies of Men
Nine: Disorders of the Penis, Scrotum, and Testicles
Ten: Sexuality and Reproduction
Eleven: The Prostate: Benign Disorders
Twelve: Prostate Cancer
Thirteen: Disorders of the Kidneys and Bladder
Fourteen: Other Male Medical Problems
Epilogue: Preventive Maintenance: Medical Care for Men
Sources for More Information