Dr. Marianne Legato seeks more research on physiological difference

One day soon, when you go to look up a drug in the Physician’s Desk Reference, there will be two kinds of clinical trial data and two sets of dosing regimens: one for men and one for women.

Increasingly, research efforts are finding that the differences between men and women extend far beyond the obvious to affect every physiological function and organ, including the heart, brain and aging process.

Helping to hasten that day and promoting that research is Marianne Legato, M.D., a Columbia University professor who also maintains a private practice in New York. She never intended to be a pioneer. It just turned out that way. "Just a few years ago," she recalls, "I was a conventional academic physician and believed that studying a phenomenon in one sex, preferably male, would be adequate for both men and women."

Then in 1991, Dr. Legato was asked by Carol Coleman, a journalist referred by the American Heart Association, to co-author a book on women and coronary artery disease.

"I asked her why?" recalls Dr. Legato. "I said, we already know all about coronary artery disease — we’ve studied it in men, and what’s different about women? She said, ‘Why don’t you do the research with me and then see what you think?’

"So many things were different about the experience of disease as a function of the sex of the patient, I couldn’t believe it. We finished the book in six months, and the experience changed my life."

What Dr. Legato discovered is that in the normal physiology of men and women, there are striking differences. Women’s hearts beat faster. The configuration and activity of some of the ionic channels in the cardiac cell membrane are different in men and women ("which explains the normal difference in the EKG between men and women"). Men’s brains are larger, but women’s brains contain more neurons. Different areas of the brain light up in response to an identical task. Age-related changes differ in men and women.

The book, The Female Heart: The Truth About Women and Heart Disease, won the 1992 American Heart Association’s Blakeslee Award (named for Alton Blakeslee, a science reporter for The New York Times).

Today, Dr. Legato, professor of clinical medicine at the College of Physicians & Surgeons at Columbia University, New York, also serves as director of the Partnership for Women’s Health at Columbia. She has become an advocate of the need for recognition that many diseases and medication affect women differently. She has also raised millions of dollars in research support from corporate sponsors.

"We in medicine have held on to a fallacy for a long time: that whatever we know about men’s physiology and reactions to medication could be extrapolated to women without modification," says Dr. Legato.

Even medical educators who focus on women’s health often don’t address this problem. "Many conferences on women’s health really reflect the ‘bikini view’ of women," Dr. Legato points out. "That is, we talk about reproductive biology, we talk about fertility issues, we talk about breast cancer, contraception and hormone replacement therapy. But we seldom include sessions on the differences in brain patterns between men and women. We don’t talk about the differences in physiology of the gastrointestinal tract. Granted, this is a very young science and we don’t know very much, but we should be making every effort to get beyond reproductive biology in women."

Dr. Legato has also done a film on the subject: Shattering the Myths: Women and Heart Disease, which won first prize in the category of Women’s Health at the 1995 International Health and Medical Film Festival.

She has gone on to publish more books on the topic, including, What Women Need to Know and Gender-Specific Aspects of Human Biology for the Practicing Physician, both in 1997.

That same year Dr. Legato founded the Partnership for Women’s Health, a liaison between the academic research community and corporations to look at the differences between men and women. The goal: to "try to correct male models of health and disease — and to develop focused products that will be more effective, based on the new information we get," she explains.

Dr. Legato is assisted by associate directors John P. Bilezikian, M.D., a Columbia professor who is an authority on bone, and Michael R. Rosen, M.D., professor of pharmacology and pediatrics at Columbia.

The pioneering team has launched a new journal, The Journal of Gender-Specific Medicine , now in its second year, with Dr. Legato as editor-in-chief, and a newsletter, Gender-Specific Medicine Digest. The Partnership also held its first annual conference in September in Orlando, FL, which is expected to become an annual event.

Dr. Legato met with Medical Tribune last month to discuss her work.

Medical Tribune: How did you go from writing a book on women and coronary artery disease to virtually starting up a whole new discipline on this topic, with its own journal and conferences?

Dr. Legato: One of the judges for the Blakeslee Award at the AHA was an advisor to Procter & Gamble. He suggested that I think about becoming a consultant in women’s health for P&G. I took him up on it and went to see the director of corporate new development at P&G. But I said to him, "Instead of acquiring one or more consultant, why don’t you consider forming an in-depth partnership with academic medicine and study the differences between men and women because that’s where the new frontier is in healthcare." It took me three years to convince them. I finally went to the chairman and chief executive officer at that time, John Pepper, who became an enthusiastic advocate of the idea. He gave me the first $2.5 million.

MT: Do you have other corporate supporters?

Dr. Legato: Yes. P&G is anxious for this not to be solely its enterprise, so partly through P&G’s efforts, we were able to gain the support of the Kellogg Foundation, Hoechst Marion Roussel, and, recently, Pfizer and Nike. Wyeth-Ayerst has supported some of our activities, and so have AstraZeneca and Bayer.

Because the Partnership is a liaison between the academic research community and several private corporations, one of our goals is to help develop focused products, based on any new information we get, that will be more effective for women. It’s a win-win project: the corporation wins, in that it has access to state-of-the-art information and it gets to develop more focused and suitable products. We profit because they help support investigations into this very new area. And because it’s such a new area, there’s a wealth of discovery to be made.

MT: How many members does the Partnership have at present?

Dr. Legato: I believe it’s about 50 physicians. We have a group of researchers and educators, specialists in various disciplines from around the world, whom we’ve designated as Partnership scholars. They’re mainly from Columbia University, but we also have some from Yale, Harvard and all over the country. And hopefully we’ll have some from all over the world as we grow.

MT: There are obvious differences between men and women, but that’s not what we’re talking about here, right?

Dr. Legato: We’re not talking about reproductive biology. We’re talking about substantive, important differences between men and women in every system of the body, from the central nervous system to the gut, to the skin, to the way in which we metabolize drugs. If you take the lipids from a female rat, for example, and imbed male enzymes in that, it feminizes drug metabolism.

MT: Why are clinical trials done mostly on men?

Dr. Legato: Since the end of World War II and the Nuremberg trials, most civilized nations have tried to protect what they consider vulnerable populations, and that may be the beginning of our effort to sequester women, especially pre-menopausal women, from the onset of being part of a clinical study. If the fetus is conceived during a drug trial, for example, who bears the consequences if that fetus is malformed? In the distilbesterol scandal, where women were given this hormone during pregnancy, it turned out their adult children were affected, and that gives people pause. Like someone said, it will take just one more thalidomide scandal to once again banish women from clinical trials until they are postmenopausal.

MT: Should women be included in clinical studies or not?

Dr. Legato: Either we have to find better ways of testing drugs without using patients in huge numbers, or we have to come to grips with the moral and legal implications of the fact that we may compromise the reproductive capacity of both young men and women when we study them. That’s what drug trial is about, to find out if it’s safe. We have to grapple with the issue of liability — moral, ethical and fiscal. Should the drug company pay if there is damage? The ill effects giving distilbesterol to pregnant women were not evident until the children were in their twenties.

MT: What are you working on now?

Dr. Legato: We’re assembling a database, available on the Web that scholars and researchers can use. If they want to know the differences between men and women in, say, bone, they can go to the bone database. There’s another one on nutrition. We have two segments finished. It’s open to anyone, they just have to register.

No one has ever done a database like this before. I thought that before we started out to do new research, it would be useful to know how much we already knew — and didn’t know we knew. It’s been very hard to do this database, because nobody has made gender an important variable.

When all the segments are finished, the scientific advisory committee will issue a position paper telling what the most important differences between men and women are in each field. Then we will issue a request for proposals addressing the topics we think would be most useful to study.

MT: What are some of the major questions out there now in gender-specific medicine?

Dr. Legato: One question for which we have a research proposal out is whether testosterone or the mechanism of testeosterone’s action in the brain controls libido, and what differences it may have, at the molecular level, on men and women. Testosterone stimulates libido in women, and testosterone deficiency in postmenopausal women is an important cause of loss of interest in sexual activity.

?We’d also like to solve why women are more prone to death from certain anti-arrhythmic agents that cause a specific arrhythmia in them called Torsade de Pointes. Michael Rosen, M.D., has been doing some interesting research on the modulating influence of gonadal steroids on electrical activity of the heart. He has found that there are gender-specific differences in the electrical behavior of conducting tissue in the heart, and he is studying that by using a gender-neutral model, a castrated rabbit. He takes tissue from the animal, exposes it to either testosterone or estrogen and looks at the impact of that on electrical activity and behavior. He’s finding that there are important differences depending on what kind of hormone the tissue is exposed to.

Other interesting gender research is being done by John Bilezikian, M.D., associate director of the department of medicine here at Columbia, who has been looking at osteoporosis in both men and women.

MT: Why hasn’t the issue of gender-specific medicine been addressed before?

Dr. Legato: The U.S. Public Health Service issued a statement only in 1988 that women were understudied. The current interest in women’s health is a direct outgrowth of feminism.

Many of the movers and shakers in medicine are not yet convinced that men and women are so different that we have to change anything about the way we care for patients outside of the reproductive realm — because the science isn’t there. My task is to make a case for the intellectual value of studying this topic.