USC Health Now

Researchers are exploring soy as a way to promote good health among postmenopausal women.

USC Health Magazine
Fall 2004
by Alicia Di Rado

When the soybean was first introduced to the United States in the 19th century, it occupied a special place: as an ornamental plant in the garden.

Times have changed.

Today, the bountiful bean not only provides protein-filled food for millions, but it is used to make a vast array of consumer goods, from crayons to car parts.

And that is not all. Researchers at the Keck School of Medicine of USC and other institutions are exploring soy’s potential to boost health.

The National Institutes of Health (NIH) is sponsoring a clinical trial at the Keck School that explores the health effects of soy in postmenopausal women. Funded at $7.5 million for 2 1/2 years, the trial will examine whether soy can influence cardiovascular health, bone strength, thinking and memory, menopausal symptoms, breast density, as a marker of breast cancer risk, and other issues related to a woman’s wellbeing.

Howard N. Hodis, M.D., professor of medicine and preventive medicine at the Keck School, is principal investigator of the new Women’s Isoflavone Soy Health, or WISH, trial, which is supported by the NIH’s National Center for Complementary and Alternative Medicine.

“This is the first randomized, double-blind, placebo-controlled long-term study on soy protein isoflavones and vascular disease and other postmenopausal health-related issues,” says Hodis, director of the USC Atherosclerosis Research Unit. “We’re very fortunate to be selected to do this trial.”

It makes sense that the NIH selected the USC Atherosclerosis Research Unit to stage the much-needed project. Building on a rich history of steady research contributions in the field of cardiovascular disease prevention and women’s health issues, the atherosclerosis team is focusing on reducing atherosclerosis in postmenopausal women through alternatives to current hormone therapy.

Millions of women have taken hormone replacement therapy (HRT), a combination of estrogen and progestin, to ease symptoms of menopause. Over the last several years, however, highly publicized trials such as the Women’s Health Initiative, and the way data from those trials have been widely interpreted—or misinterpreted, Hodis says—have made many women shun HRT altogether.

As a result, researchers have begun looking for ways to promote good health among postmenopausal women without using traditional HRT. Soy might be a candidate, but without conducting careful studies, physicians cannot know for certain.

“On the heels of the controversies surrounding HRT, there really is probably no other alternative available for women looking for postmenopausal comfort and health,” says Hodis, who also is professor of molecular pharmacology and toxicology at the USC School of Pharmacy. Clearly, research on soy’s effects is important for women’s future welfare.

Fighting plaque

Over the years, cholesterol-laden plaques accumulate along the inner lining of artery walls. Called atherosclerosis, this build-up process narrows the space where blood can travel. Bits of atherosclerotic plaque may even break off, traveling down the blood stream until they get stuck and stem blood flow.

Atherosclerosis may not be a household word, but the events that result from it—heart attack and stroke—certainly are. Cardiovascular disease, after all, is the number-one cause of death among American women.

Before women reach menopause, the estrogen that naturally courses through their bodies protects them from cardiovascular disease. But after menopause, when their bodies’ estrogen levels plummet, atherosclerosis progresses more quickly and cardiovascular disease risk rises.

Mounting research hints that substances in soy, called isoflavones, might help the vascular system much like estrogen does. Paradoxically, isoflavones seem to act like human estrogen sometimes, and then act opposite the hormone at other times.

“With these isoflavones, it seems to be a mixed mechanism,” says Hodis, noting that they are much weaker than human estrogen. “They stimulate genes that are positive upstream, and block genes that are negative downstream.”

Hodis will use noninvasive imaging to measure the thickness of artery walls in participants over the course of the study, hoping to see if the artery walls of women who eat soy thicken more slowly than those of women who are not eating soy.

“Soy’s mechanisms of action have not been fully elucidated yet,” Hodis says. “But we’re excited to be on the way to learning more.”

Soy slowdown

Probably the most active area of research relating to soy and health, says Hodis, has been the field of breast cancer.

And Keck School of Medicine researcher Anna H. Wu, Ph.D., has played a big part in creating that activity.

A professor of preventive medicine, Wu teamed with fellow researchers Malcolm Pike, Ph.D., and Brian E. Henderson, M.D., now dean of the Keck School, to conduct one of the first studies on breast cancer among middle-aged Asian women.

In the dietary part of that study, Wu asked women whether they ate tofu—a seemingly throwaway question, since tofu is such a staple in the Asian diet. But surprisingly, she saw that Asian women in the study who developed breast cancer ate considerably less tofu than the Asian women without cancer.

Since then, epidemiologists and scientists have been looking closer at soy’s benefits.

For example, Wu and her colleagues have interviewed more than 2,000 Los Angeles women over eight years to learn about the implications of their consumption of certain foods, including soy. The case-controlled study compares 1,200 Asian women in Los Angeles who have had breast cancer to another 1,200 cancer-free women. Results are expected soon.

Wu also worked with Mimi Yu, Ph.D., Keck School professor of preventive medicine, to study postmenopausal women in Singapore. They found that those who eat more soy foods have lower levels of estrone, a type of estrogen, circulating in the blood.

Evidence suggests that the more exposure to estrogen, the greater the breast cancer risk. The ovaries produce estrogen, which travels through the blood to the breast and other tissues. Estrogen stimulates breast cells to divide and multiply. The more breast cells multiply, the greater the chance that genetically faulty cells will arise. Cancer results when abnormal cells multiply out of control.

In the WISH study, Wu wants to see if eating soy slows down proliferation of cells in the breast. She will examine whether eating soy over time can lower the density of women’s breast tissue, as measured through mammography.

Researchers will perform mammograms on women in the beginning, middle and end of the study. Although a few studies done since 2000 have hinted that soy has little or no effect on breast density, those studies had limitations, she says. The WISH trial will provide much-needed information for scientists.

Phytoestrogen future

But female hormones such as estrogen and progestin affect more than the breast. Physicians know that they influence the endometrium, too.

The endometrium forms the inner lining of the uterus, where tissue grows and then is shed every month, following the hormonal dictates of a woman’s menstrual cycle. For more than 40,000 American women every year, though, it also is the site where cancer begins.

Juan C. Felix, M.D., professor of clinical pathology and obstetrics and gynecology at the Keck School, has been studying how hormones and substances called selective estrogen receptor modulators, such as raloxifene and tamoxifen, affect the endometrium. The soy study fits right in.

“With soy products, there is a big void of knowledge as to exactly what they do,” Felix says. Tamoxifen, for example, was found to act like estrogen in the endometrium, while it is an anti-estrogen in the breast. Physicians need to know whether soy is similar.

Already, a recent study in the San Francisco Bay area suggested that eating foods rich in phytoestrogen—a type of estrogen found in plants such as soy—might cut endometrial cancer risk, but more data is needed.

“I think we’re likely to have a positive outcome with it,” Felix says. “So if it proves to be beneficial to the cardiovascular system, I’m hopeful women will be able to use it without fear.”

Another colleague, osteoporosis specialist Robert K. Rude, M.D., professor of medicine at the Keck School, will look at whether soy can preserve women’s bones.

Bones are made up of cells that continuously break down and recreate new bone tissue. As people age, bone tissue may break down faster than it forms—leading to bone loss known as osteoporosis, which raises the risk of crippling bone fractures. Bone loss can speed up around menopause, when estrogen levels drop.

But researchers think soy might help, if its isoflavones act like estrogen to protect bones. Its mix of protein and calcium might be beneficial, too. “As osteoporosis is such a large problem, any potential preventative or therapeutic agent should be explored,” Rude says.

A few human studies have suggested that soy can protect bone density in postmenopausal women, says Rude, “but these trials were usually less than six months in duration.” Other studies have shown no effects. The WISH trial should shed more light on the topic.

Finally, biostatistician Wendy J. Mack, Ph.D., associate professor of preventive medicine and researcher with the USC Alzheimer’s Disease Research Center and Atherosclerosis Research Unit, will measure cognition in study participants over time to see if soy has any relationship to improved thinking and reduced dementia. Few studies have been done on the subject to date.

Participants will be assessed over time for concentration, language, verbal and visual memory, visualization, and executive function—the ability to manipulate information such as numbers within the mind. If the researchers see a significant problem in a patient, such as in their cognitive function, they will be referred to a physician, Mack notes.

“I’m not sure some people realize what a problem cognitive impairment poses in the U.S.,” she says. “We need more strategies to influence the trajectory of the development of these diseases.”

If soy can indeed help with cognition, as well as with the health of breast, bone, endometrium and the cardiovascular system, scientists may be able to add another item to the soybean’s already-long résumé: the ultimate super-food.

Whole hearted

Based on a body of scientific evidence, the U.S. Food and Drug Administration in 1999 approved a health claim for soy protein: “Twenty-five grams of soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease.”

Products containing at least 6.25 grams of soy protein per serving may carry the health claim on their packaging.

But scientists are unsure exactly which parts of soy protein are healthful or if soy must be solely eaten as a whole food, such as tofu, to offer benefits.

Isoflavones are one ingredient of soy protein under special scrutiny. Isoflavones are phytoestrogens—substances structurally similar to estrogen, but found in plants. Two isoflavones particularly abundant in soy are called genistein and daidzein.

Twenty-five grams of soy protein contain about 50 milligrams of isoflavones. The U.S. Department of Agriculture and Iowa State University created a database of isoflavone content in soy foods. It is available at www.nal.usda.gov/fnic/foodcomp/Data/isoflav/isoflav.html.