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Food for Thought

Concerns over Genistein, Part I—The heart of the issue

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For the past few decades, health magazines—and, more recently, health Web sites—have touted the virtues of soy. Some studies have suggested it can dramatically cut heart risks. Others describe this legume as a potentially powerful weapon against cancer. Soy beans—and the tofu, tempeh, snack "nuts," and other products made from them—have risen to become media superstars.

Consumers, however, have been somewhat slow to embrace soy products as dietary staples. One new study suggests that might be a good thing, at least for older women.

A woman's risk of developing heart disease climbs at menopause, when her body's production of estrogens wanes. Augmenting these diminishing sex hormones—in part, to protect the heart—has been one rationale for treating post-menopausal women with hormone-replacement therapy. However, because of risks associated with this therapy physicians have been reluctant to prescribe these powerful hormones during the past decade (SN: 5/31/03, p. 341).

Many plants, including soy, contain natural mimics of estrogen. Some scientists have reasoned that supplementing the diet with these plant-derived isoflavones, which include genistein, daidzein, equol, and glycitein, might also protect the heart.

That notion has made its way into the popular literature and fueled the marketing of isoflavone-rich soy products as natural, healthful alternatives to hormone-replacement therapy. Medical evidence of their benefits, however, has been weak at best, notes Carl J. Pepine, chief of cardiology at the University of Florida College of Medicine in Gainesville.

So, he and researchers from five other medical institutions decided to investigate whether women who have high concentrations of genistein in their blood—indicative of higher dietary intakes of "estrogens" from soy and other plants—would have better vascular health. They tested that hypothesis in women who had recurrent chest pain, which is a symptom of incipient heart disease.

The opposite of their hypothesis proved true, they now report in the May Journal of Women's Health. High genistein levels correlated with poor cardiovascular health.

"There are a lot of women taking these things [isoflavone-rich products], without any direct evidence that they're beneficial," Pepine notes. The new study, he says, adds to a small but growing body of research suggesting there could be a down side to overindulging in them.

WISE findings

Pepine's group evaluated the role of plant estrogens among participants of the Women's Ischemia Syndrome Evaluation (WISE) project. Funded by the National Institutes of Health and begun more than a decade ago, WISE has recruited more than 900 women to investigate whether heart disease tends to develop differently in them than it does in men.

There's reason to suspect that it might: Several studies have shown that most women who experience recurrent chest pain don't have evidence of obstructed vessels to the extent that men do. It could be that the obstructions are merely harder for doctors to spot in women, for some reason. But it's also possible that women develop a different type of vascular disease. For instance, small vessels may not adjust their diameters, from moment to moment, as readily as they do in men. Such constant vascular responsiveness is essential to meeting the varying oxygen needs of tissues.

Women participating in the WISE project do show far less obstruction of the coronary arteries than is typical of men with heart disease, as has been found in other studies. Moreover, women in this study—and several others—have shown less vascular responsiveness than is typical in men with cardiovascular disease.

In addition to testing vascular responsiveness in the women, the WISE project has been exploring the role of natural sex hormones and their mimics—like soy's plant estrogens—in the development of heart disease and its manifestations.

In the new study, the researchers correlated blood concentrations of genistein against various measures of vascular responsiveness in 106 WISE participants, all women around the age of 55. Imaging tests revealed that only 24 percent of these women had obstructive heart disease. However, all of the women had reduced blood flow, a symptom of heart disease. Those whose vessels were least able to relax, dilate, and increase flow rate in response to changing physiological needs tended to have the highest blood concentrations of genistein.

Ordinarily, Pepine explains, a vessel should be able to dilate enough to triple or even quadruple its normal rate of blood flow. This permits substantially greater oxygenation of tissues fed by that vessel. However, in the new WISE analysis, women with the poorest vascular responsiveness couldn't even double blood flow within small vessels. As a woman's blood concentrations of genistein fell, however, the ability of those coronary microvessels to dilate increased. Some were able to triple their flow rates.

What's happening?

Blood vessels have different layers. The interior one, which is in contact with the blood, is known as the endothelium. In response to changes in blood flow and blood pressure, its cells can release chemicals—principally nitric oxide—that can penetrate into the vessel wall and relax smooth-muscle cells that make up the middle vessel layer. The tension or relaxation of these muscle cells controls a vessel's diameter and blood-flow rate.

Some problems in vascular responsiveness trace to the endothelium. Other problems can stem from damage to the smooth-muscle cells themselves. In the new study, Pepine's group investigated both systems.

Pepine had expected the epithelium, which comes into direct contact with plant estrogens in the blood, to prove more sensitive to genistein concentrations. In fact, both vessel layers appeared sensitive, Pepine told Science News Online, although "we saw the biggest effect at the muscle-cell level. That was definitely a surprise."

One possibility, he says, is that plant estrogens block chemical receptors on smooth-muscle cells that recognize adenosine. That compound, a byproduct of chemicals released by the heart, is believed to play a pivotal role in vessel dilation, he explains.

If that is indeed the problem, he says, then reducing exposure to these plant estrogens may improve small-vessel responsiveness.

Currently, the WISE investigators can't point to soy specifically as the source of the genistein measured in the studied women because the researchers didn't obtain detailed dietary histories before the participants were tested. It's not that the scientists weren't interested, Pepine says, but a matter of expediency. Participants of the complex study completed many tests and questionnaires. In fact, the one probing characteristics of a woman's chest pains was itself 12 pages long. Asking for detailed dietary information just seemed to be too much of an imposition on the study's volunteers, he says.

However, dietary sources of plant estrogens are something his team plans to investigate in the future. The researchers also plan to randomly assign some women to diets enriched with genistein, and others to meals low in it. That's the only way to tell whether such plant estrogens actually impair vascular responsiveness. It could rule out the possibility that WISE volunteers who experienced the most discomfort due to vascular unresponsiveness were those most driven to find an over-the-counter remedy—like soy foods or food supplements containing soy isoflavones.

In the meantime, nobody has to give up soy-based foods. However, I'm going to continue dining on them in moderation.


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Citations

Carl J. Pepine

Division of Cardiovascular Medicine

University of Florida College of Medicine

P.O. Box 100277

Gainesville, FL 32610-0277
Further Reading

Egashira, K., et al. 1993. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. New England Journal of Medicine 328(June 10):1659-1664. Available at [Go to].

Harder, B. 2003. Unproven elixir. Science News 163(May 10):296-297. Available at [Go to].

______. 2002. Look Ma, too much soy: Hormone in infant food reduces immunity in mice. Science News 161(May 25):325. Available at [Go to].

Helmuth, L. 1999. Nutritionists debate soy's health benefits. Science News 155(April 24):262. Available at [Go to].

Raloff, J. 2003. Soy greens—The coming health food? Science News Online (July 5). Available at [Go to].

______. 2001. Soy slashes cancer-fostering hormones (with recipe). Science News Online (March 24). Available at [Go to].

______. 2000. Soy land, soy land. Science News Online (Oct. 14). Available at [Go to].

______. 2000. Soy, tea, and cancer benefits. Science News 157(May 13):312. Available at [Go to].

______. 1999. Soy slows growth of prostate cancers. Science News 156(Nov. 6):295. Available at [Go to].

______. 1999. Soy's anticancer surprise. Science News 155(May 15):319. Available at [Go to].

______. 1999. Soy compounds help preserve bone. Science News 155(Jan. 2):15. Available at [Go to].

______. 1998. Soya-nara, heart disease. Science News 153(May 30):348-349. Available at [Go to].

Seppa, N. 2003. Flawed therapy: Hormone replacement takes more hits. Science News 163(May 31):341. Available to subscribers at [Go to].

______. 2002; Hormone therapy falls out of favor. Science News 162(July 27):61. Available at [Go to].

______. 2001. Soy estrogens: Too much of a good thing? Science News 159(June 16):375. Available to subscribers at [Go to].

Sharaf, B.L., C.J. Pepine, et al for the WISE Study Group. 2001. Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation [WISE] study angiographic core laboratory). American Journal of Cardiology 87(April 15):937-941. Abstract available at [Go to].

Simon, J.A., et al. 2001. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-progestin Replacement Study (HERS). Circulation 103(Feb. 17):638-642. Available at [Go to].

Steinberg, K.K., et al. 1991. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. Journal of the American Medical Association 265(April 17):1985-1990. Abstract available at [Go to].

For information about the WISE Study, go to [Go to].

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