Judy Foreman

Nationally Sindicated Fitness, Health, and Medicine Columnist

Thyroid, Cholesterol Are Linked

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Most Americans know by now that eating a diet high in saturated fat can raise cholesterol, a major risk factor for heart disease, which kills nearly 500,000 people a year and is the leading cause of death for both men and women.

But what many people don’t know is that an underactive thyroid – the butterfly-shaped gland in the neck that produces a crucial hormone that regulates metabolism – may also contribute to high cholesterol.

When thyroid hormone levels are too low, the liver makes fewer molecules called LDL receptors, whose job is to pull LDL, or “bad” cholesterol out of the blood. The result is an increase in cholesterol levels. A low thyroid level can also mean high levels of triglycerides – fatty acids that also contribute to heart disease.

Some data suggest that only 5 percent of people with high cholesterol have an underactive thyroid but several studies put the figure as high as 14 percent, said Dr. Lewis Braverman, chief of the endocrine, diabetes and nutrition section atBoston Medical Center. An underactive thyroid is easily treatable with supplemental thyroid hormone, and when it is,cholesterol levels often return to normal.

But, while doctors routinely screen for cholesterol, many don’t do simple blood tests for thyroid levels, even when an elevated cholesterol level should be a signal to do so. Nearly 100 million Americans have cholesterol levels that are either high (240 milligrams per deciliter and up) or borderline (200 to 239 mg per dl), according to the American Heart Association.

There’s a strong economic argument for being more aggressive about detecting and treating potential thyroid problems in people with elevated cholesterol. Thyroid drugs such as Synthroid or Levoxyl cost less than $100 a year. By contrast, the class of cholesterol-lowering drugs called “statins,” which includes Mevacor and Pravachol, can cost many times that.

But there’s an even more compelling medical argument. Better detection and treatment of hypothyroidism, or underactive thyroid gland, could not only lower cholesterol and thereby reduce the risk of future heart disease, but make millions of people feel better.

An estimated 13 million Americans, many of them women over 50, suffer from hypothyroidism, though many don’t know it because symptoms can be mild at first and are often chalked up to aging or “the blues.” The symptoms include fatigue, forgetfulness, depression, chilliness, weight gain, and goiter (an enlarged thyroid gland), as well as elevatedcholesterol.

Another 2 million Americans, many of them women aged 20 to 40, have the opposite problem – an overactive thyroidgland, which causes nervousness, weight loss, intolerance to heat and goiter.

Both hypothyroidism and hyperthyroidism can result from a misguided attack by the body’s immune cells and antibodies on the thyroid gland – in the first case, inhibiting or destroying the gland; in the second, forcing it into high gear.

Testing for thyroid problems is fairly straightforward – a blood test for TSH, or thyroid stimulating hormone, which is made by the pituitary gland. When the pituitary gland senses that the body is not making enough thyroid hormone, TSH levels rise, signaling the thyroid gland to make more.

If a TSH test comes back abnormal, the doctor usually does another test for blood levels of thyroid hormone itself. If TSH is high and thyroid hormone levels are low, it’s a clear sign that supplemental hormones are needed to get things back in balance. A person also clearly needs treatment if the reverse is true – low TSH and high thyroid levels.

But many people, especially those with “subclinical” hypothyroidism, have more ambiguous test results – typically an elevated TSH but normal levels of thyroid hormone itself. Some doctors advise treating this form of mild disease, while others hold off, arguing that when the disease is still too mild to cause symptoms, treatment may not help.

If your cholesterol is high, ask your doctor for a thyroid test if he or she hasn’t suggested it already.

You may have to fight for the thyroid test, though, because some insurers balk at paying for routine thyroid screening, noted Dr. Richard A. Dickey, an endocrinologist at Wake Foreest University in Winston-Salem, N.C, and president of the American Association of Clinical Endocrinologists.

Still, it’s important to find out because doctors need to “eliminate secondary causes of high cholesterol, which include low thyroid function,” says Dr. David Gordon, a heart researcher at the National Heart, Lung and Blood Institute.

It also works the other way around, said Dr. Peter Wilson, an endocrinologist at the Framingham Heart Study. If you are tested for thyroid function and that is low, ask to be tested for cholesterol, too.

Calculating The Risks Of Hormone Therapy

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It takes a village, or so they say, to raise a child.

Well, it’s beginning to take a whole village – and a high-tech one at that – to sort out the risks and benefits of hormone-replacement therapy.

Luckily, there is such a village. It’s at New England Medical Center in Boston, where Drs. Nananda Col, John Wong, and Stephen Pauker in the Division of Clinical Decision Making have created a mathematical model to see how the benefits of hormone therapy – such as reduced risk of osteoporosis – stack up against the risks, including breast cancer, for a hypothetical 50-year-old woman at average risk of both diseases.

But their endeavor has its limits. Chief among them is that the estimates they feed into their computers come from observational studies, and not randomized, double-blind, placebo-controlled trials, the “gold standard” of medical research.

That means their data are derived from women who chose to take hormones at menopause.

In general, women who choose hormones are better educated and have better health habits than women who don’t, which can skew the results of observational studies, noted Dr. JoAnn Manson, an endocrinologist and chief of preventive medicine at Brigham and Women’s Hospital in Boston.

A better sense of the true risks and benefits of hormone therapy is expected in 2005, when the results of the massive, $625 million Women’s Health Initiative are in.

In that trial, which involves 27,000 women at medical centers around the country, volunteers are randomly assigned to take hormones or placebo for an average of nine years. Since the women who take hormones and those who don’t are otherwise similar, differences in subsequent disease risk are probably due to hormones – or lack of them.

But, for many women, five years is too long to wait for guidance, so we asked Col to use her model to run projections of risks and benefits 10 and 20 years from now for a 50-year old woman at average risk of breast cancer, hip fracture, uterine cancer, and coronary disease (defined as nonfatal heart attack, clogged arteries, chest pain or sudden cardiac death).

Because models only work if one plugs in certain assumptions, Col decided that, to be as representative as possible, our 50-year-old would have a total cholesterol of 239 milligrams per deciliter and systolic blood pressure (the top number on a blood pressure test) of 134 millimeters of mercury.

In addition, instead of flipping a coin to decide whether our heroine should have the health risks of a smoker or nonsmoker, and of a diabetic or nondiabetic, Col gave her 44 percent of the disease risks that go with smoking and one-eighth of those due to diabetes. Col also assumed the woman had no family history of heart disease or osteoporosis.

Lastly, because 20 percent of the population has a mother, sister or daughter with breast cancer, Col assumed our hypothetical woman had a 20 percent chance of such a family history, too. She also assumed there was a 28 percent chance that our woman had one breast biopsy and that she had her first child between ages 25 and 29.

Col then calculated the woman’s chances of getting breast cancer, uterine cancer, a hip fracture or heart disease in the next 10 and 20 years, and the odds of her dying from those diseases under different scenarios – no hormone replacement therapy, combination therapy with two hormones (estrogen and progestin) for 10 or 20 years, or estrogen alone for 10 or 20 years. (Progestin is added to hormone therapy to protect the uterus from cancer in women who have not had a hysterectomy.)

The data that Col fed into her computer was derived from several large observational studies, including the Nurses’ Health Study and a major study on breast cancer risk published recently in the Journal of the National Cancer Institute.

In these studies, women took the standard dose of estrogen (usually 0.625 milligrams a day of Premarin), and if they took progestin, it was 5 to 10 milligrams a day of Provera.

Col also fed into her model the risks and benefits associated with a newer hormonal therapy called raloxifene (Evista) instead of estrogen. (Raloxifene’s advantage is that, unlike estrogen, it can lower the risk of osteoporosis without raising the risk of breast or uterine cancer.) She did likewise with alendronate (Fosamax), a non-hormone drug that protects the bones and has no known effect on breast cancer, uterine cancer or heart disease.

The results were intriguing. Ten years from now, our hypothetical woman’s risk of getting breast cancer was clearly lower (one in 45) if she took estrogen alone than if she took estrogen and progestin (one in 37), much as two recent studies in JNCI and the Journal of the American Medical Association showed.

But what shows up even more dramatically in Col’s model is the bigger difference in risk of uterine cancer depending on whether a woman takes estrogen alone or with progestin. The risk of uterine cancer over 10 years is one in 19 if a woman takes estrogen alone, compared to one in 102 if she takes it with progestin.

That’s a strong reason, Col said, for women not to act on fears generated by the recent studies and dump combination therapy in favor of estrogen alone.

Manson, the Brigham and Women’s endocrinologist, agreed. Manson, who is one of the chief investigators in the Women’s Health Initiative, said she fears some women in that study may drop out because of concern about the risks of combination therapy. But there are two different ways to take combination therapy – a woman can take both hormones every day, or sequentially – estrogen every day and progestin only part of the month.

The former is thought to be safer – and, in fact, in the recent JNCI study, the risk of breast cancer was lower in women who used the simultaneous therapy than in the sequential therapy group, though this did not quite reach statistical significance.

Another observation for our mythical matron is that the benefits of hormone therapy in preventing hip fracture grow with time and become more pronounced after 20 years. “And if you go out to the next 30 years, it’s even bigger,” Col said.

With heart disease, the benefits appear to kick in earlier and persist as long as a woman takes hormones. Heart disease is both more common and more likely to be lethal than breast cancer.

In Col’s model, Fosamax, the osteoporosis drug, was comparable to hormone therapies in reducing the risk of hip fractures without raising the risk of breast cancer.

Raloxifene, the hormonal alternative to estrogen, lowers the risk of hip fracture without raising breast cancer risk, but does not help much with heart disease risk. (And some younger women who try raloxifene quit because, like some who take a similar drug called tamoxifen, they simply do not feel as well on it.)

In five years, if all goes well with the Women’s Health Initiative, there will be better ways to assess the risks and benefits of hormone therapy. And that study should answer other questions as well, such as whether hormone therapy reduces the risk of cognitive problems and Alzheimer’s disease and how hormones affect mood, sleep and other quality-of-life issues.

The expectation is that the benefits of hormone therapy will outweigh its risks for most women, Manson said.

Until then, we’re in the land of educated guesses. And women who would like to do less guessing can have their doctors contact the decision-making gurus at the New England Medical Center (hrt@lifespan.org). 

HPV Test Is Urged By Some

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The Pap smear, used to detect cervical cancer, is done 50 million times each year in the United States and remains one of the best cancer-detection tools doctors have.

In the 50 years since it was introduced in the United States, the death rate from cervical cancer has dropped by 70 percent. In poor countries that don’t yet do Pap screening, cervical cancer is a leading cause of cancer death in women.

But the Pap test, which involves scraping cells from the cervix and examining them under a microscope, is far from perfect. About 25 percent of the time, it misses abnormalities. And 3 million times a year, it yields such ambiguous findings that doctors aren’t sure how to proceed.

That’s where a relatively new test – to detect human papilloma virus or HPV – may help significantly.

Though many women don’t realize it, scientists now know that 99 percent of cases of cervical cancer are caused by persistent infection with certain high-risk strains of HPV.

Many women – in fact, a majority of young women – are at least transiently infected with HPV, which is transmitted sexually. In many, a vigorous immune response fights off the virus before it can trigger the genetic changes that lead to cervical cancer. But, in others, HPV infection does lead to cervical cancer, which strikes 13,000 American women a year and kills 5,000.

The mildly abnormal Pap tests that have long had doctors – and women – in a quandary, are typically low-grade lesions that probably would never become cancer. They’re often dubbed ASCUS, for “atypical squamous cells of undetermined significance.”

There’s agood chance that these mild abnormalities will go away by themselves in a year or so.

But since the lesions may be a precursor to cancer, doctors never know whether it’s better to send a woman for more invasive – and expensive – testing and treatment, or just repeat the Pap test in six months.

Hopefully the answer to that will come next year when results of a trial of 5,000 women with mild cervical abnormalities conducted by the National Cancer Institute are in. In the meantime, some doctors are already urging women with mildly abnormal Pap tests to have the HPV test.

The test, made by the Digene company of Beltsville, Md., was approved for use in conjunction with Pap smears a year ago by the US Food and Drug Administration and has been shown to be a highly sensitive test.

The new thinking goes like this: If the Digene test shows no HPV infection in a woman with a mildly abnormal Pap smear, it’s probably safe to just repeat the Pap test in six months.

If the Digene test does show HPV infection, it may make sense to have a more invasive procedure called colposcopy, in which the doctor examines the cervix with a high-powered microscope and takes a small sample of tissue. If that biopsy is precancerous, the woman would go back to have her cervix treated by freezing or have the abnormal cells cut out with a wire loop. If it is outright cancer, she would probably need a hysterectomy or radiation treatments.

Some gynecologists, like Dr. Diane McGrory of Dedham Medical Associates and Newton-Wellesley Hospital, already use HPV testing routinely in women with mildly abnormal Pap tests. Several medical centers, including those at Yale, Johns Hopkins and the Cleveland Clinic, are also working with Digene to expand HPV testing.

McGrory, who serves on the medical advisory board for Digene, says that just by identifying women who do not need colposcopy, HPV testing serves a major purpose. Colposcopy costs several hundred dollars and can cause pain and anxiety as well.

Adding the HPV test to Pap testing does add $35 to $50 to the costs, she noted, and some insurers do not pay for the HPV test. But doing the HPV test is cheaper than sending women for unnecessary colposcopies, she argued.

Furthermore, it’s increasingly easy to combine the HPV test with a relatively new Pap test called ThinPrep because the same sample of cervical cells can be used for both tests.

(ThinPrep is part of an emerging type of Pap testing called liquid-based cytology, in which cells from the cervix are put into a vial of solution instead of being spread immediately on a microscope slide. The vial is shaken to separate cervical cells from mucus and blood. The cells are then spread in a thin layer – one cell thick – on the slide, making it easier to read than the often-lumpy traditional smear. Researchers are now working on ways to get computers to read the thinner Pap tests.)

To some cancer specialists, however, it’s too soon to urge HPV tests at the first sign of a mildly abnormal Pap test. It simply won’t be known whether this is the best or most cost-effective approach until the NCI study is completed next year, said Dr. Diane Solomon, who co-directs that study.

The American College of Obstetricians and Gynecologists is also holding off on recommendations on HPV testing, as is the National Women’s Health Network, a Washington-based advocacy group.

Still others, like Dr. Robert Burk, a medical geneticist at the Albert Einstein College of Medicine in New York, take a middle course. The issue, as Burk sees it, is whether a woman has a transient or persistent infection with HPV.

Many women – and men, too – become temporarily infected with HPV during sex, he said, even if they use condoms, because the virus can be spread by mere contact with genital skin, not just with intercourse. Though there is no treatment for HPV, infections often disappear in nine months as the immune system fights off the virus. (In men, the virus only rarely leads to penile cancer.)

If the infection persists, genes from the virus may integrate into the DNA of cervical cells, though this can take 10 years or more. The virus then churns out proteins called E6 and E7 that bind to proteins called p53 and Rb, which block cancer. Once binding occurs and this cancer protection is lost, cervical cells may accumulate other genetic changes that lead them to grow uncontrollably. Some strains of HPV – notably HPV-16 – are especially dangerous, Burk said.

To tell whether a woman who has one positive HPV test has a persistent or transient infection, doctors could re-test for HPV in six to 12 months. If the same strain of HPV is present on both tests, she may have a persistent infection that could trigger cancer. If she tests negative, or has a different strain on the second test, she may not have a persistent infection.

But Burk, and many other researchers, do not yet recommend HPV testing in all women with mildly abnormal Pap tests, in part because HPV infection is so common, especially in young women, that the test wouldn’t mean much. In one study of 608 female college students in New Jersey, for instance, 70 percent were infected with HPV.

Instead, Burk believes a wise course would be to use the HPV test in older women who have mildly abnormal Pap tests. For younger women, repeating the Pap test in six months is fine.

Ultimately, the HPV test could even replace the Pap test, some researchers say, especially in countries where women don’t get Pap tests now. Two studies, published in January in the Journal of the American Medical Association, support this.

One study, by National Cancer Institute researchers, looked at 8,554 women in Costa Rica who were screened with the HPV test. It found HPV testing was more sensitive than conventional Pap testing.

The other, by researchers at Columbia University, studied 1,415 women in South Africa and found that even when women collected their own cervical samples for HPV testing, the test was as sensitive as Pap smears at detecting high-risk cervical disease.

Ultimately, the HPV test could be used as a screening test in the United States, too, and could even be sold over the counter so that women could test themselves for HPV infection.

Even before then, one thing already seems clear: Women who are faced with an ambiguous finding on a Pap test should at least ask their doctors about HPV testing before agreeing to more invasive procedures like colposcopy.

The saga of soy. That soy is good is partly right

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Consumers Believe Soy Is Good Food, And Research Shows They’re Partly Right.

Americans have fallen in love with the humble soybean. Convinced that in its many incarnations – tofu, soy milk, dietary supplements – soy can prevent everything from heart disease to hot flashes to cancer, consumers have sent soy sales soaring.

In the 12 months ending in October 1999, supermarket sales of soy foods were up 45 percent over the previous year, to nearly $419 million, according to Spins, a San Francisco market research company.

But is soy really as beneficial as people believe and as some ads say?

The most solid evidence of soy’s benefit comes from studies of cholesterol. In October, the US Food and Drug Administration was convinced enough of its benefit to begin letting manufacturers put health claims on soy products indicating that soy may lower heart disease risk.

Some studies suggest soy can fight hot flashes and may lower the risk of breast and prostate cancer. But paradoxically, the very ingredients that make soy beneficial may endow it with risks.

Soybeans are legumes that are rich in plant estrogens, specifically, genistein and daidzein, which are substances known as isoflavones. Like the estrogens that humans make in their bodies or buy by prescription, phytoestrogens may drive cell proliferation – a red flag that means soy could theoretically spur cancer growth, particularly breast cancer, which is often driven by the hormone estrogen.

In general, because soy isoflavones are weak estrogens, they may be taken in by molecules known as estrogen receptors, possibly blocking the stronger estrogens made in the body.

In premenopausal women, this means that plant estrogens may protect against breast cancer by blocking a woman’s own, stronger estrogens; in postmenopausal women, who have less estrogen than younger women, adding plant estrogens to the diet could yield an overall increase in estrogen levels, a possible concern for women who have or may develop breast cancer.

So how do the plusses and minuses of soy stack up in all areas of health? Much of it depends on individual risk factors for various diseases. Here’s the latest data to go on:

Cholesterol. Overall, human and monkey studies suggest that soy reduces cholesterol 10 to 15 percent, a figure that reflects a grab-bag of studies on tofu, soy powder, extracts, and supplements. Specifically, soy lowers LDL or “bad” cholesterol, and countries where people eat a lot of soy tend to have lower heart disease rates, as well as lower cholesterol.

To get the beneficial effect of soy, a person has to eat at least four servings containing 6.25 milligrams of soy protein a day, as part of a diet low in saturated fat and cholesterol, the FDA noted.

In other words, soy provides “a definite, but modest reduction” in cholesterol, says Dr. Sherwood Gorbach, a professor of community health and medicine at Tufts University School of Medicine, who has also developed and patented a soy supplement called Healthy Woman.

Bone density. Here, the studies are mixed, with some showing a protective effect and others not. Some preliminary data suggest soy may restore bone loss, but this is not proved.

Hot flashes and other menopausal symptoms. Again, the data are mixed. Some data suggest soy reduces hot flashes by 40 to 50 percent, says Dr. Machelle Seibel, an endocrinologist at the Fertility Center of New England in Dedham and medical director of Inverness Medical, Inc., which makes SoyCare supplements.

But hot flashes often improve by 20 to 30 percent on placebo (or dummy drugs), too, he notes, adding that in some women, soy probably adds 20 to 30 percent to the benefit from any placebo.

On the other hand, Margo Woods, a Tufts nutritionist, has just completed a study of 85 women and found no difference between soy protein and placebo – both reduce hot flashes by about 25 percent, she says.

As for vaginal dryness, another common menopausal symptom, at least one study shows soy helps some women.

Prostate Cancer. Epidemiological studies from Asia suggest that men there are less likely than American men to get prostate cancer and die of it. One possible reason is that soy isoflavones may inhibit an enzyme that converts the hormone testosterone to its chemical cousin, dihydrotestosterone, which can spur prostate cell growth.

In a few case studies of men with prostate cancer, high doses of isoflavones seem to reduce the number of cancer cells, notes Seibel. So far, however, there’s no solid evidence for using soy to treat prostate cancer.

In fact, despite encouraging data from animal studies that suggest soy isoflavones also act as angiogenesis blockers (which stop blood vessel growth around tumors), so far, no company appears to have asked the FDA to approve a health claim for soy on the grounds that it may fight prostate – or any other – cancer.

Breast Cancer. This is the diciest area of all because some research suggests that soy prevents breast cancer, while other indicates that, at least theoretically, it could increase it.

On the one hand, strong epidemiological evidence from Singapore and elsewhere shows that Asian women have a three- to five-fold lower risk of breast cancer than American women, though whether this is due to eating soy is unclear. At the very least, it would seem to suggest that high, lifelong soy consumption lowers the risk of breast cancer risk.

In fact, Japanese women with breast cancer typically continue to eat soy as part of their diet – and their survival rates are better than those of American women with breast cancer.

Furthermore, research suggests that in postmenopausal women, the levels of estradiol, a natural estrogen made in the body, decrease while women take soy, suggesting that soy may be protective against breast cancer, says Woods of Tufts.

The mere suggestion that soy might increase breast cancer risk rankles some soy researchers, including Gorbach of Tufts. “That’s a ridiculous contention,” he says. “Everywhere in the world where soy is consumed, the amount of breast cancer is remarkably decreased.”

Still, in the interests of full disclosure, here’s another side of the story.

When human breast cancers are transplanted into mice who are then given varying doses of isoflavones, strange things happen, says Tufts biochemist Barry Goldin. At high doses, the plant estrogens inhibit the growth of human breast cancer cells, while at lower doses, they may enhance it.

At the University of California in San Francisco, Dr. Nicholas Petrakis, an emeritus professor of preventive medicine and epidemiology, has also studied American women given soy and found some had an increase in the number of hyperplastic, or potentially precancerous, breast cells as well. This does not prove that soy raises the risk of breast cancer, he cautions, but it does suggest that soy probably has a “stimulatory estrogenic effect.”

Also troubling is a 1998 study of nearly 50 premenopausal women published in the American Journal of Clinical Nutrition. The women were randomly assigned to continue their normal diets or to add 60 grams a day of soy supplements (containing 45 milligrams of isoflavones) for 14 days. Those who added soy had a greater increase in proliferation of breast cells.

Bobbie Hayes , a nurse in the menopause consultation service of Harvard Vanguard Medical Associates, puts it this way: “We don’t feel [soy] is completely benign.” It may be that soy is protective in Asian women who consume it all their lives, she says, but not for American women who start taking large doses at menopause to combat hot flashes.

At the National Cancer Institute, Dr. Peter Greenwald, director of the division of cancer prevention, adds that women who take soy are “taking an estrogenic compound. We know estrogens promote breast cancer and cell proliferation. So there is a theoretical risk.”

Unfortunately, he adds, so far “we have no evidence” from clinical trials on either “the benefits or the harm of soy. If women are taking it to combat hot flashes, I would not see a problem with short-term use – a year or six months.. . .I think the longer you go, the less sure we are without studies.”

Bill Helferich, a professor of nutrition at the University of Illinois, shares that concern. If given early in life, he says, isoflavones can cause breast tissue to differentiate, just as estrogen does – a good thing because the more differentiated breast cells are, the less likely they are to become cancerous.

On the other hand, if taken later in life, when tiny tumors may already be starting to grow, plant estrogens may cause those tumors to grow faster, he says.

Of particular concern, Helferich says, is women who take the prescription drug tamoxifen to prevent breast cancer but who want to switch to soy. That makes no sense, he says, because tamoxifen is a proven way to reduce cancer risk and soy is not.

So what’s the bottom line in terms of breast cancer? Given that nobody has proved that soy reduces or raises breast cancer risk, much less that the supplements have the same risk-benefit profile as soy food, the prudent course might be for women to make decisions about soy just as carefully as they would about prescription estrogen. Among other things, that might mean talking to your doctor about taking soy for a limited period of time to combat hot flashes, then stopping.

And what about food versus supplements? Alas, once again, there are no good data, but Woods, the Tufts nutritionist, says that “people should increase their consumption of soy as a food,” she says. “It’s better than hamburger or fried chicken.”

Most of the data showing a benefit to soy come from studies of food, not pills. “We have no data on what happens when you take phytoestrogens as supplements. . . I think taking supplements is too big a leap from the data on food.”

If you want to add soy to your diet, try adding about three ounces of tofu or its equivalent a day, which will give you 45 milligrams of soy phytoestrogens, the amount that’s believed to be beneficial to the heart.

If you prefer supplements instead, you should aim for about 45 to 55 mg a day. And it may be best to break this into two doses, one in the morning, one at night.

The Saga Of Soy

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Consumers Believe Soy Is Good Food, And Research Shows They’re Partly Right.

Americans have fallen in love with the humble soybean. Convinced that in its many incarnations – tofu, soy milk, dietary supplements – soy can prevent everything from heart disease to hot flashes to cancer, consumers have sent soysales soaring.

In the 12 months ending in October 1999, supermarket sales of soy foods were up 45 percent over the previous year, to nearly $419 million, according to Spins, a San Francisco market research company.

But is soy really as beneficial as people believe and as some ads say?

The most solid evidence of soy’s benefit comes from studies of cholesterol. In October, the US Food and Drug Administration was convinced enough of its benefit to begin letting manufacturers put health claims on soy products indicating that soy may lower heart disease risk.

Some studies suggest soy can fight hot flashes and may lower the risk of breast and prostate cancer. But paradoxically, the very ingredients that make soy beneficial may endow it with risks.

Soybeans are legumes that are rich in plant estrogens, specifically, genistein and daidzein, which are substances known as isoflavones. Like the estrogens that humans make in their bodies or buy by prescription, phytoestrogens may drive cell proliferation – a red flag that means soy could theoretically spur cancer growth, particularly breast cancer, which is often driven by the hormone estrogen.

In general, because soy isoflavones are weak estrogens, they may be taken in by molecules known as estrogen receptors, possibly blocking the stronger estrogens made in the body.

In premenopausal women, this means that plant estrogens may protect against breast cancer by blocking a woman’s own, stronger estrogens; in postmenopausal women, who have less estrogen than younger women, adding plant estrogens to the diet could yield an overall increase in estrogen levels, a possible concern for women who have or may develop breast cancer.

So how do the plusses and minuses of soy stack up in all areas of health? Much of it depends on individual risk factors for various diseases. Here’s the latest data to go on:

Cholesterol. Overall, human and monkey studies suggest that soy reduces cholesterol 10 to 15 percent, a figure that reflects a grab-bag of studies on tofu, soy powder, extracts, and supplements. Specifically, soy lowers LDL or “bad” cholesterol, and countries where people eat a lot of soy tend to have lower heart disease rates, as well as lower cholesterol.

To get the beneficial effect of soy, a person has to eat at least four servings containing 6.25 milligrams of soy protein a day, as part of a diet low in saturated fat and cholesterol, the FDA noted.

In other words, soy provides “a definite, but modest reduction” in cholesterol, says Dr. Sherwood Gorbach, a professor of community health and medicine at Tufts University School of Medicine, who has also developed and patented a soysupplement called Healthy Woman.

Bone density. Here, the studies are mixed, with some showing a protective effect and others not. Some preliminary data suggest soy may restore bone loss, but this is not proved.

Hot flashes and other menopausal symptoms. Again, the data are mixed. Some data suggest soy reduces hot flashes by 40 to 50 percent, says Dr. Machelle Seibel, an endocrinologist at the Fertility Center of New England in Dedham and medical director of Inverness Medical, Inc., which makes SoyCare supplements.

But hot flashes often improve by 20 to 30 percent on placebo (or dummy drugs), too, he notes, adding that in some women, soy probably adds 20 to 30 percent to the benefit from any placebo.

On the other hand, Margo Woods, a Tufts nutritionist, has just completed a study of 85 women and found no difference between soy protein and placebo – both reduce hot flashes by about 25 percent, she says.

As for vaginal dryness, another common menopausal symptom, at least one study shows soy helps some women.

Prostate Cancer. Epidemiological studies from Asia suggest that men there are less likely than American men to get prostate cancer and die of it. One possible reason is that soy isoflavones may inhibit an enzyme that converts the hormone testosterone to its chemical cousin, dihydrotestosterone, which can spur prostate cell growth.

In a few case studies of men with prostate cancer, high doses of isoflavones seem to reduce the number of cancer cells, notes Seibel. So far, however, there’s no solid evidence for using soy to treat prostate cancer.

In fact, despite encouraging data from animal studies that suggest soy isoflavones also act as angiogenesis blockers (which stop blood vessel growth around tumors), so far, no company appears to have asked the FDA to approve a health claim for soy on the grounds that it may fight prostate – or any other – cancer.

Breast Cancer. This is the diciest area of all because some research suggests that soy prevents breast cancer, while other indicates that, at least theoretically, it could increase it.

On the one hand, strong epidemiological evidence from Singapore and elsewhere shows that Asian women have a three- to five-fold lower risk of breast cancer than American women, though whether this is due to eating soy is unclear. At the very least, it would seem to suggest that high, lifelong soy consumption lowers the risk of breast cancer risk.

In fact, Japanese women with breast cancer typically continue to eat soy as part of their diet – and their survival rates are better than those of American women with breast cancer.

Furthermore, research suggests that in postmenopausal women, the levels of estradiol, a natural estrogen made in the body, decrease while women take soy, suggesting that soy may be protective against breast cancer, says Woods of Tufts.

The mere suggestion that soy might increase breast cancer risk rankles some soy researchers, including Gorbach of Tufts. “That’s a ridiculous contention,” he says. “Everywhere in the world where soy is consumed, the amount of breast cancer is remarkably decreased.”

Still, in the interests of full disclosure, here’s another side of the story.

When human breast cancers are transplanted into mice who are then given varying doses of isoflavones, strange things happen, says Tufts biochemist Barry Goldin. At high doses, the plant estrogens inhibit the growth of human breast cancer cells, while at lower doses, they may enhance it.

At the University of California in San Francisco, Dr. Nicholas Petrakis, an emeritus professor of preventive medicine and epidemiology, has also studied American women given soy and found some had an increase in the number of hyperplastic, or potentially precancerous, breast cells as well. This does not prove that soy raises the risk of breast cancer, he cautions, but it does suggest that soy probably has a “stimulatory estrogenic effect.”

Also troubling is a 1998 study of nearly 50 premenopausal women published in the American Journal of Clinical Nutrition. The women were randomly assigned to continue their normal diets or to add 60 grams a day of soysupplements (containing 45 milligrams of isoflavones) for 14 days. Those who added soy had a greater increase in proliferation of breast cells.

Bobbie Hayes , a nurse in the menopause consultation service of Harvard Vanguard Medical Associates, puts it this way: “We don’t feel [soy] is completely benign.” It may be that soy is protective in Asian women who consume it all their lives, she says, but not for American women who start taking large doses at menopause to combat hot flashes.

At the National Cancer Institute, Dr. Peter Greenwald, director of the division of cancer prevention, adds that women who take soy are “taking an estrogenic compound. We know estrogens promote breast cancer and cell proliferation. So there is a theoretical risk.”

Unfortunately, he adds, so far “we have no evidence” from clinical trials on either “the benefits or the harm of soy. If women are taking it to combat hot flashes, I would not see a problem with short-term use – a year or six months.. . .I think the longer you go, the less sure we are without studies.”

Bill Helferich, a professor of nutrition at the University of Illinois, shares that concern. If given early in life, he says, isoflavones can cause breast tissue to differentiate, just as estrogen does – a good thing because the more differentiated breast cells are, the less likely they are to become cancerous.

On the other hand, if taken later in life, when tiny tumors may already be starting to grow, plant estrogens may cause those tumors to grow faster, he says.

Of particular concern, Helferich says, is women who take the prescription drug tamoxifen to prevent breast cancer but who want to switch to soy. That makes no sense, he says, because tamoxifen is a proven way to reduce cancer risk andsoy is not.

So what’s the bottom line in terms of breast cancer? Given that nobody has proved that soy reduces or raises breast cancer risk, much less that the supplements have the same risk-benefit profile as soy food, the prudent course might be for women to make decisions about soy just as carefully as they would about prescription estrogen. Among other things, that might mean talking to your doctor about taking soy for a limited period of time to combat hot flashes, then stopping.

And what about food versus supplements? Alas, once again, there are no good data, but Woods, the Tufts nutritionist, says that “people should increase their consumption of soy as a food,” she says. “It’s better than hamburger or fried chicken.”

Most of the data showing a benefit to soy come from studies of food, not pills. “We have no data on what happens when you take phytoestrogens as supplements. . . I think taking supplements is too big a leap from the data on food.”

If you want to add soy to your diet, try adding about three ounces of tofu or its equivalent a day, which will give you 45 milligrams of soy phytoestrogens, the amount that’s believed to be beneficial to the heart.

If you prefer supplements instead, you should aim for about 45 to 55 mg a day. And it may be best to break this into two doses, one in the morning, one at night.

Facial Workouts Don’t, In Fact, Really Work At All

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I sat there glued to the TV, trying to imitate the model on the video, who was cheerily flexing her zygomaticus muscles – which run from the cheekbone to the corners of the lips – and keeping the rest of her face relaxed.

Not so easy. Then she worked her levator labii superioris, raising her lips up into a sneer. Then she attacked her chin, working the depressor labialis.

We should be doing these exercises 10 to 15 minutes a day, six days a week, according to the narrator, a 71-year-old British lady named Eva Fraser, who’s about to launch in this country the “facial fitness” program she’s promoted for years in England.

On the video, Fraser, who looks closer to 50, spoke through clenched teeth, her face barely moving. Were her muscles so exhausted from all her facial workouts that she could no longer move them?

No, she was not her usual animated self in the video, she explained in a telephone interview, because she was trying to keep still so the microphone didn’t pick up extra noise.

In any case, her take-home message seemed to make sense: Weak muscles, sagging face; strong muscles, a young, vibrant one.

Too bad it’s not true.

The real problem when faces droop with age, it turns out, is loss of collagen in the skin, the pull of gravity on fascia (that gristly tissue that lies between muscles and skin), and the loosening of facial ligaments.

And, sadly enough, exercise is useless for collapsing collagen, falling fascia and lax ligaments.

That means, at least as doctors see it, that not only won’t facial fitness do you much good, neither will those mouth-stretching gadgets called Facial Flex, advertised in magazines and the Internet, or electrical stimulation devices like those also touted on the Net by Boulder, Colo., esthetician Kay Young.

Now, you could take the cynical – or is it the hopeful? – view that dermatologists and plastic surgeons would naturally dump on exercise and other do-it-yourself tricks because they can make a fortune doing chemical peels, facelifts, and other nips and tucks that may hide the ravages of age.

But the doctors make a pretty good case against facial workouts.

Exercising may “work partly,” concedes Dr. Jessica Fewkes, a dermatologist at the Massachusetts Eye and Ear Infirmary in Boston. “It can work on the part of the face that is due to just sagging muscles. . . . But a lot of our drooping skin isn’t necessarily due to muscles; a lot of it is due to photoaging.”

Photoaging is caused by exposure to sunlight. The ultraviolet light destroys the elastic fibers in skin that hold it together, causing the collagen to become much thinner.

“When you pinch a baby’s cheek,” Fewkes says, “it has a nice, solid feel to it. When you pinch your mother’s skin, it’s thin. It’s missing that layer. That’s not muscle we’ve lost, it’s collagen.”

That’s why “the number-one thing for looking good is sun protection,” she adds. Indeed, people with darker skin, like blacks and Asians, “tend to look younger longer because they have so much pigment in their skin they don’t get the same radiation damage.”

Exercising facial muscles “really won’t do anything for the sagging face,” says Dr. Devinder Mangat, a Cincinnati plastic surgeon and president of the American Academy of Facial, Plastic and Reconstructive Surgeons.

Jowls, for instance, which often run in families, are caused “almost 100 percent by displacement of the `SMAS’ [or superficial muscular aponeurotic system] layer of fascia,” says Dr. Mack Cheney, director of facial and cosmetic surgery at Mass. Eye and Ear.

In a face lift by plastic surgery, it’s this layer of tissue that is “redraped” over bone and muscle to tighten sagging cheeks, says Cheney.

And facial exercises could make some problems worse.

Horizontal lines in the forehead are caused by the frontalis muscle. “The stronger this muscle gets, the deeper the creases,” says Cheney. “So strengthening the frontalis muscle is a negative thing. It will make furrows deeper.”

Short of a face lift, what may help for forehead furrows, including vertical ones in the corrugator muscles between the eyebrows, is botox, or botulism toxin. While botulism is fatal if injected in high doses, in the tiny doses injected cosmetically, it can paralyze the frown muscles for a few months without causing harm.

Puffy eyes aren’t caused by muscle weakness, either, even though the eyes are surrounded by the orbicularis oculi muscle.

The problem with droopy eyelids – upper and lower – lies with a ligament-like structure called the orbital septum, which lies just below the muscles, and stretches with time.

“Exercises wouldn’t help that,” he says. “It’s not muscle that’s holding the orbital fat, which produces the puffiness. It’s this ligament-like structure.”

And what of those Facial Flex gadgets that you put in your mouth to exercise muscles in the lower face? The ads tout research suggesting these gadgets can increase muscle strength by 250 percent.

Sorry, they can’t. “If you’re trying to get improvement in skin and fascia, a stronger muscle won’t do that,” says Cheney.

And electrical stimulation to tone the face? “That is unlikely to help, either,” he says.

The bottom line is simple. Forget facial workouts. You’ll have to love the face you’ve got – unless you choose to go under the knife.

St. John’s Wort: Less Than Meets The Eye

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Globe Analysis Shows Popular Herbal Antidepressant Varies Widely In Content, Quality.

We thought it would be easy.

After all, we had just two seemingly simple questions: Does St. John’s wort, the popular herbal adtidepressant on which Americans spend $250 million a year, work – at least on rat brain cells in a test tube? And do the product labels accurately reflect what’s inside the tablets?

The path toward answers proved tortuous indeed.

We hired two companies, Paracelsian, Inc. of Ithaca, N.Y., and PhyttoChem Technologies Inc., of Chelmsford, Mass., to independently test seven St. John’s wort products we purchased and repackaged into bottles coded by number. The companies didn’t know it at the time, but we also sent each one an eight product, a placebo or inert drug, supplied to us by the Massachusetts College of Pharmacy.

We found that there was considerable chemical and biological variation among the products tested.

We’ll give you tyhe bottome line next – but read on, because the caveats are important.

On the basis of the PhytoChem analysis, only one product, Nature’s Resource, lived up to the standard claim on product lables that the products contain 0.3 percent of hypericin, a substance once thought to be the active ingredient in St. John’s wort. (Now, to be the active ingredient, but the industry continues to standardize products to 0.3 percent of hypercin.)

Four other products, Natrol, NatureMade, Herbalife, and YourLife, were lower in hypericin, containing 0.28 percent, 0.27 percent, 0.25 percent, and 0.25 percent, respectively – less than their labels claimed.

With prescription drugs, the US Food and Drug Administration allows products to contain slightly less (10 percent below) to slightly more 10 percent above) than the contents stated on the label.

With diatary supplements, the FDA insists that they contain at least 100 percent of what’s declared on the label, but because the agency does not require supplements to meet the same strigent requirements for safety and efficacy that it does for drugs, it does not specify what tests should be used to measure herbal ingredients or which labs should do them.

Although many of the products we tested fell short of their labeling numbers using the PhytoChem test, they might have passed with other testing methods in other labs.

One product, Quanterra, contained almost no hypericin, but its label makes no claim that it does.

According to the Paracelsian biological assays, only two products, Quanterra and NatureMade, passed the company’s “BioFIT” test for their ability to block the reuptake of both serotonin and dopamine, two neurotransmitters involved in depression.

(Abnormalities in the reuptake, or absorption, of serotonin and other neurotransmitters are believed to be a major cause of depression; many prescription antidepressants work by blocking the reuptake of serotonin into brain cells, thus leaving more in the synapse, or gap, between cells.)

John Cardellina, vice president for botanical sciences at the Council for Responsible Nutrition, which represents 100 manufacturers of dietary supplements, said the Globe’s chemical analysis actually “doesn’t look bad for the industry.” While only one product had as much hypericin as it listed on the label, “everybody was close to the mark. There’s not much to complain about.”

The biological assay, he felt, was more controversial. Paracelsian’s BioFIT test is “not yet an accepted practice or marker,” said Cardellina. One limitation is that, by measuring serotonin and dopamine reuptake, the test focuses on only “one of multiple mechanisms of action by which St. John’s wort works.” Another, of course, is that it is conducted in a test tube and does not involve human subjects.

Still, the fact that only two products – NatureMade and Quanterra – passed the BioFIT test is noteworthy. “Frankly, I’d expect to see more activity in that assay,” Cardellina said.

When we shared our findings with manufacturers of the products we tested, some reacted with vigorous criticism.

Although its products fared better than most, Pharmavite, which makes NatureMade and Nature’s Resource, noted there is always variability in chemical tests of herbal products. The company added it does “not believe that the data provided offers a reliable indicator of the quality of any of the brands tested.”

It also said it had “significant concerns about the manner in which the tests were conducted and the apparent reliance on limited and possibly unsubstantiated test methodology in forming any conclusions about product quality.”

On the other hand, Michael Cleary, director of product development for Natrol, Inc., welcomed our findings. “I think it’s pretty healthy” to do such a study, he said. “There was not any hint of any unfairness in any of this.”

Furthermore, he said, “To tell the truth, we expect people to pull our product off the shelf, and if they have it analyzed, to find what the label claims.”

And to many of those familiar with the largely unregulated herbal industry, including the heads of the two testing companies we hired, our findings appeared to come as no shock at all.

“It’s not surprising that few of these compounds passed,” said Timothy Maher, director of pharmaceutical services at the Massachusetts College of Pharmacy, one of our independent data reviewers.

“People are buying these products and not always getting what they pay for,” added Bernie Landes, the CEO of Paracelsian, one of the testing companies.

Even Robert Barry, the president of PhytoChem but a strong critic of our study, said that in the industry as a whole, more “rigorous study needs be done – 80 to 90 percent of what’s out there has not been subjected to tests to see whether they provide a physiological effect.”

Even if, as some in the industry point out, the bioassay used by Paracelsian measures only one of several possible mechanisms of action of St. John’s wort, and even if the chemical analysis by PhytoChem had built-in limitations, our study nevertheless shows that quality control in herbal products is a big problem.

“You have demonstrated quite nicely with this study that there is lot of variation in St. John’s wort products. I am concerned about patients self-treating a serious illness like depression with products whose contents they cannot count on,” said Dr. Serena Koenig, a physician at Brigham and Women’s Hospital in Boston who studies drug and herbal remedy interactions.

“Quality control is the number one issue in the herbal industry, no question about it,” acknowledged Mark Blumenthal, executive director of the American Botanical Council in Austin, Texas, a nonprofit research and education organization funded in part by the herbal industry.

A big part of the problem, he added, “is the lack of federal or industry policies, regulations, or requirements that stipulate a particular method of analysis for SJW [St. John’s wort] and other herbs.”

The FDA does not require that herbal remedies, which are sold as dietary supplements, be approved for safety or efficacy before they are marketed. And it allows them to stay on the market unless there is evidence of harm.

Using PhytoChem’s data, we did our own calculation and found that one product, Nature’s Resource, actually had slightly more hypericin, 0.31 percent, than its label claimed. We calculated the percent hypericin in product extracts so consumers could compare this to the 0.3 percent hypericin stated on most labels.

But PhytoChem became uneasy. In a Dec. 17 letter, PhytoChem president Barry expressed “very grave concerns regarding any conclusions that may be drawn from the very limited testing that our company was asked to peform on the Saint [sic] John’s wort products supplied by the Boston Globe.”

In interviews and in writing, Barry also expressed his strong belief that the proper methodology would have been to have both the chemical and the biological evaluations “conducted by three independent laboratories,” with at least one being a lab with no commercial interest in product testing.

Both PhytoChem and Paracelsian have a commercial interest in testing herbal products. Paracelsian plans to use its bioassay called BioFIT to provide a seal of approval for manufacturers to put on product labels. PhytoChem tests products under development for herbal and pharmaceutical companies.

Still, others in the herbal industry saw things more positively.

“I think of all the analyses done by the media, this is one of the more intriguing approaches because you have asked for chemical analysis and have looked at the emerging technology for a biological assay of the physiological activity” as well, said Cardellina of the Council for Responsible Nutrition.

“By pairing the content [chemical testing] and the activity question [biological testing], you did a good thing. . .I don’t think you can go beyond that without running a clinical trial.”

Dr. Scott Ewing, director of the depression and anxiety disorders clinic at McLean Hospital in Belmont, Mass., and a St. John’s wort researcher, wondered why the BioFIT assay looked at dopamine, a neurotransmitter that may not play as big a role in depression as serotonin, and not at epinephrine, which does play a role. (Curiously, most products we tested fared better on the dopamine test than on the serotonin assay, though it’s not clear why.)

In any case, says Ewing, the BioFIT data on dopamine “may not have any real, practical significance in terms of antidepressant effects.”

Perhaps also puzzling was the fact that there was little overlap between the biological and chemical results. Paul Blum, another of our independent data reviewers and a neuroscientist and pharmaceutical consultant in Cambridge, Mass., did a statistical analysis of the correlation of the chemical and biological findings and found “the two tests don’t correlate well with each other.”

This could be explained, however, if the chemical for which PhytoChem tested, hypericin, is not the active ingredient in St. John’s wort and some other ingredient, such as hyperforin, is.

Some of the variance in hypericin content that we found may be due to differences in raw materials and testing methods, noted Blumenthal of the American Botanical Council.

In its Dec. 9 letter to us, PhytoChem explained that it had used a spectrophotometric method called DAC 1991 to test for hypericin. Some companies test their products using an earlier test, DAC 1986. And it makes a difference.

“While not all the products passed the PhytoChem test based on the DAC 91 method, all but one would have passed by the DAC 86 standard, except for the CVS product, which comes very close,” said Blumenthal.

“Today, you can call up supply houses that sell St. John’s wort extract and you can buy two grades, one at 0.3 percent hypericin as determined by the DAC 1986 method, and the other, by the DAC 1991 method, which costs more. Therein lies part of the problem.”

Because the price difference can be as much as 30 percent, some manufacturers may buy material that meets only the easier, 1986 standard, “especially with no industry or government-mandated standards for one or the other,” said Blumenthal.

In part because of such problems, the industry is currently moving away from DAC testing toward a more precise, quantitative version of high-performance liquid chromatography testing, said Cardellina of the nutrition council.

Some of the product variance we found may also be due to other factors. St. John’s wort “is sensitive to extremes of temperature,” said Ewing, the McLean psychiatrist. It’s also sensitive to light and to humidity. That means samples “left for many months on pharmacy shelves tend to degrade and therefore lose their potency.”

Ultimately, the solution to quality control problems in the herbal industry is probably tighter regulation – of both manufacturing and labelling. If the government won’t do it, consumer pressure may force the industry to do so.

In fact, a Denver firm, Industrial Laboratories, has formed the Institute for Nutraceutical Advancement, which is funded by the herbal industry to validate methods for testing products.

Blumenthal, of the American Botanical Council, welcomes such efforts. Hopefully, he said, “one of the results of this Globe study will be to hasten the adoption by industry organizations of uniform methods of labelling standardized products – an issue that the industry has been working on for some time.”

How the Globe did its testing

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Here’s how we tested some of the leading brands of St. John’s wort, the popular herbal antidepressant.

We went to a CVS store in Cambridge, Mass., and bought the following products: CVS’ house brand; Natrol; NatureMade; Nature’s Resource; Quanterra; and YourLife. In addition, we obtained a bottle of Herbalife, which is sold privately through distributors.

We placed several pills of each brand in two sets of unmarked, identical-looking bottles and coded each brand. The CVS brand, for instance, became BG-001 (for Boston Globe), Herbalife became BG-002, etc.

We then sent one set of coded samples to an herbal testing company in Ithaca, N.Y. called Paracelsian, Inc. and hired it to do biological assays. The goal was to see whether each product worked – as judged by its ability to block the “reuptake” (or absorption) of both serotonin and dopamine, two neurotransmitters involved in depression, in rat brain cells in a test tube.

We sent the other samples to a testing company called PhytoChem Technologies, Inc. in Chelmsford, Mass., and hired it to do a chemical analysis of each of the products. The goal was to see if the products had as much hypericin, an ingredient in St. John’s wort, as the labels indicated.

In addition, unbeknownst to either company, we included an eighth set of pills in each set, placebos, or “dummy” pills, supplied to us by the Massachusetts College of Pharmacy. This was a way of testing the tests – a placebo should not pass the biological assay (and it didn’t) nor should it have a chemical profile like that of real St. John’s wort products (and again, it didn’t.)

After we got the results, we analyzed them with the help of independent scientists, including Paul S. Blum, a neuroscientist in Cambridge, Mass., who helps drug companies develop new drugs, and Timothy Maher, director of pharmaceutical sciences at Massachusetts College of Pharmacy.

We also discussed our results with the manufacturers of all the products we studied and herbal industry spokespeople.

 

Details of the testing methods: In the biological analysis, Paracelsian compared each product to Prozac and Zoloft (prescription antidepressants known as selective serotonin reuptake inhibitors) and to a “reference” herbal product, the Perika brand of St. John’s wort, which has been shown to inhibit the reuptake of the neurotransmitters serotonin and dopamine in rat studies, and to reduce mild to moderate depression in some people.

Prozac and Zoloft work by blocking the reuptake into brain cells of serotonin, and to a lesser extent, by blocking dopamine as well. Paracelsian’s assumption was that if St. John’s wort works, it may act by this same mechanism, that is, blocking neurotransmitter reuptake.

The Paracelsian scientists took cells from rats’ brains and put them in a test tube with a sample of St. John’s wort. They then added serotonin and calculated how much was left in the test tube after several minutes. The more that is left in the test tube, the better the antidepressant effect.

The Paracelsian team then repeated this for dopamine.

In the chemical analysis, PhytoChem did two tests on each sample – a spectrophotometric assay (called DAC 1991) and HPLC, or high performance liquid chromatography.

In the first, PhytoChem passed light through each sample.

Because scientists know what wavelengths of light hypericin absorbs, they can calculate how much hypericin is in a product – the more light absorbed, the more hypericin the product contains. For each sample, PhytoChem did this test twice and then averaged the results. PhytoChem also compared each result to the amount of light absorbed by a known control substance.

In the second test, the HPLC, PhytoChem injected each sample into a stainless steel column packed with silica (like powdered glass or sand). The silica was then treated with a special surface coating. The individual substances in St. John’s wort were then separated based on how well they stuck to this coating.

As individual compounds are separated out and leave the column, they can be detected by the absorption of light. The resulting pattern of peaks exiting the column at particular times and different intensities of light absorption produce a “chromatogram” – essentially a “fingerprint” of the constituents of a particular plant. The “fingerprint” of St. John’s wort is clearly different from that of, say, ginseng.

(We used only the first type of chemical testing, the spectrophotometric method, to gauge the amount of hypericin in each product. We did not use the HPLC test results to calculate hypericin; we used it only in a qualitative sense. It showed that all of our sample products except the placebo had the typical St. John’s wort fingerprint.)

Strengths of our study: We used two different companies for biological and chemical testing and independent consultants to help analyze the results. We blinded the testing companies to the identity of the products. We also did not tell them we had submitted placebos. And we bought the products as any consumer might – in a popular drug store.

Drawbacks of our study: Our study was not a clinical trial in humans, we did not re-confirm our results with other testing companies, and we did not test all available brands, including two major products, Kira and Movana.

The Paracelsian assay may not test the correct mechanism for St. John’s wort. While some scientists think St. John’s wort works by blocking serotonin reuptake, others are unconvinced. That means some samples that flunked the Paracelsian test might pass a test based on another mode of action.

The PhytoChem analysis isn’t perfect, either. It tested our samples for hypericin, which scientists used to think was the active ingredient in St. John’s wort. Now, some scientists think the active ingredient may be a chemical called hyperforin.

Still, hypericin is the ingredient manufacturers use to standardize products and it’s the one that’s touted on the labels.

Go the medical route if herb doesn’t relieve depression

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So, you’re depressed. Given that the Globe’s analysis showed that, at least in lab tests, there is considerable variation among St. John’s wort brands, should you take it at all?

Buying any herbal remedy is basically a crapshoot. But the short answer is that if you try a brand of St. John’s wort and it helps within about three weeks, stick with it. Your improved mood might be due to the placebo effect – you feel better because you expect to feel better. In studies in which neither depressed patients nor doctors know who is getting a real drug and who is getting a harmless substitute, 55 to 65 percent of patients feel better on a placebo, at least for a limited time.

And in a sense, who cares? Feeling better is what counts.

If, on the other hand, you take St. John’s wort for a few weeks and still feel depressed, stop fooling around with self-medication, get to a doctor and ask about a prescription drug such as Zoloft or Prozac and/or psychotherapy.

Whatever you do, don’t take St. John’s wort and a prescription antidepressant without checking with a doctor. There are now reports of three cases of “serotonin syndrome,” a potentially fatal excess of serotonin, in people who combined St. John’s wort with a prescription antidepressant.

In a year or so, there should be more definitive answers on how well St. John’s wort works, when a $3.6 million study sponsored by the National Institute of Mental Health is completed. Led by researchers from Duke University, this study involves scientists at 12 centers nationwide, including McLean Hospital in Belmont, Mass., and will involve 336 patients who are taking St. John’s wort, Zoloft, or a placebo.

The Duke study is using a brand of St. John’s wort called Kira, made by Lichtwer Pharma AG. This is the brand that has been studied the most in Germany, where St. John’s wort is widely used.

Kira was not one of the products we tested. It contains an extract of St. John’s wort called LI 160. This extract contains hypericin and hyperforin, a compound many researchers now believe is essential to St. John’s wort efficacy.

Through its corporate ties to another German pharmaceutical company, Dr. Willmar Schwabe GmbH & Co., Lichtwer allows its LI 160 extract to be used as the basis for another St. John’s wort product, Quanterra, whose label states that it contains a variant of the extract called LI 160 WS, which means vitamin C has been added to stabilize hyperforin.

Even without the Duke study, this is already some evidence for the potential benefits of St. John’s wort for depression.

In 1996, German researchers pooled data from 23 short-term studies (using different brands of St. John’s wort) and found that it helps with mild to moderate depression; it was more effective than placebo and equivalent to standard prescription drugs.

“What is impressive is that the vast majority of studies do suggest that St. John’s wort has real antidepressant effects. If, in fact, this was nothing more than placebo, we would not expect to see such consistent results,” says Dr. Scott Ewing, director of the depression and anxiety disorders clinic and a St. John’s wort researcher at McLean. “Having said that,” he warns, “virtually all of the studies have been methodologically flawed in one respect or another.” In fact, that’s one reason why NIMH decided to sponsor the Duke study.

Anecdotally, there’s lots of support for St. John’s wort. “I’ve talked to 25 or 30 people who’ve tried it,” says Dr. Jonathan Cole, a McLean psychiatrist who is participating in the Duke study. About 15 thought it helped, he said.

“One of my informants had gotten very depressed after her pet died. She kept crying and crying. She took St. John’s wort and stopped crying. After a month, she figured she was over it and stopped taking it. She started crying again. She stopped crying again” when she resumed St. John’s wort, he said.

On the other hand, Ewing says that in his clinical experience, results “have been somewhat disappointing. Very often, people may be doing little more than giving themselves a rather expensive placebo because the substance may have lost its potency” because it’s sensitive to temperature and other factors. (St. John’s wort prices vary, but run about $1.00 a day, compared to Prozac, which can cost $5 and up a day.)

In addition to the Duke study, other research on St. John’s wort is underway or has been recently completed.

In a Massachusetts General Hospital study funded by Lichtwer, Dr. Jerry Rosenbaum, a psychiatrist, is comparing Kira to Prozac and placebo, with neither patients nor doctors knowing which patients are getting which substance.

At McLean, Ewing has just completed a study in which patients and doctors did know that all the patients were getting St. John’s wort, a brand called Alterra. “We haven’t analyzed all the data yet,” he says, but 70 to 80 percent of the 40 patients responded to the herb. He is now starting a double-blind study of 80 patients in which some will get St. John’s wort and some a placebo.

So the data aren’t all in. But at the moment, the bottom line remains: If you take St. John’s wort and it helps, great. If you try it and it doesn’t, get to a doctor for more proven remedies.

FDA loosens reins

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The US Food and Drug Administration once had the power to force manufacturers of over-the-counter dietary supplements, including herbal remedies, to prove those products were safe, if the agency felt such a pre-market review was warranted.

That changed in 1994, when Congress passed the Dietary Supplement Health and Education Act, which gives sellers of vitamins and herbs the freedom to tout the alleged benefits of their products without much FDA intervention.

Since DSHEA, it’s been possible to put a supplement on the market and keep it there until the FDA finds clear evidence that the product is harmful. Unlike drugs regulated by the FDA, dietary supplements and herbs do not have to be proven to be safe or effective to be sold.

Before DSHEA, all health claims on supplements – as on food – had to have FDA approval before marketing. Since DSHEA, manufacturers have been able to make “structure/function” claims without prior approval. That means they haven’t been able to say a product prevents a particular disease, like depression, but they can say something vague like the product is a “mood enhancer.”

But the vagueness of struc ture/ function claims has caused considerable confusion among consumers. In response to that, last week, the FDA issued a new ruling on disease claims, which takes effect in 29 days.

It states that a number of common conditions such as aging and pregnancy are normal life stages, not diseases, and therefore manufacturers can make structure/function claims for products aimed at them, says Peggy Dotzel, acting associate commissioner for policy at the FDA.

But some consumer advocates say the ruling is a blow to consumer protection. The change is a “huge weakening” of the previous FDA proposal, says Dr. Sidney M. Wolfe, director of Public Health Citizen Research Group in Washington, D.C. It is “a snake-oil exemption” and a “complete cave-in to the industry.”

On the other hand, industry representatives were delighted.

“The FDA has backed down from its previous, ill-considered proposal to redefine the word `disease’ by broadening it. . .to include nonpathological states that are a normal function of aging or the body,” said Mark Blumenthal, executive director of the American Botanical Council in Austin, Texas, a nonprofit research and education organization funded in part by the herbal industry.

Under the FDA’s original proposal, “menopause would be considered a disease. Even balding and graying of a beard would have been considered a disease,” he said.

In essence, he added, the final rule now “allows herbal products to continue making certain kinds of claims that might not have been able to be made had that definition of disease gone into final status.”

With manufacturing of herbal products, DSHEA requires only that manufacturers produce them in accordance with “good manufacturing practices” of the food industry. But there is a wide range of standards within the food regulations, which are often less stringent than those in the pharmaceutical industry.

The FDA is now writing more stringent manufacturing regulations for supplements and has sought comments from supplement makers and the public.

While the United States continues to struggle with ways to regulate the herbal industry, other countries have long had a better grip on things.

In Germany, herbal products are regulated largely as pharmaceuticals – both as prescription and over-the-counter drugs, notes John Cardellina of the Council for Responsible Nutrition, a Washington-based group representing the supplement industry. But, he adds, the German “approval process for drugs is not as stringent as the FDA approval process.”