NOVEMBER / DECEMBER 2006

FORUM

Women’s health and the health of all: At the intersection of sex, gender, and medicine

Science is making it increasingly apparent that the differences between men and women are myriad and complex. Where do we go from here?

Women’s health has had a relatively short but powerful history. An outgrowth of the 1970s feminist and civil rights movements in the U.S., the field has progressed from focusing on maternal and infant mortality to spearheading major advances in reproductive health to delving into the question, biologically and sociologically, of what it means to be a woman.

It has only been around 20 years since the U.S. Public Health Service formally acknowledged that we knew almost nothing about women’s health apart from reproductive biology. Since then, discoveries in human biology have revealed that sex-based differences influence physiological functions in every system of the body, and recent breakthroughs in human genetics have begun to show us just how profound and multifaceted those influences are.

Dr. Marianne J. Legato: Women’s health should “not be in isolation” from other areas of study or practice.

“What started this whole concept of the difference between men and women was our concentrated decade of study of women,” says Marianne J. Legato, MD, founder and director of the Partnership for Gender-Specific Medicine at Columbia University’s College of Physicians and Surgeons in New York, N.Y. “We no longer assume that women are identical and interchangeable with men on a biological basis. Once we did that, we began to focus on evidence-based science in women in a way we never had before.”

As a result, we now know that among other things, women and men differ in how we develop and experience coronary disease, how diabetes affects the heart, and how the body reacts to cigarette smoking. We know that being male or female is not just a question of hormones but “imprinting” (the silencing of alleles in a small set of genes). And we know that there are variations in bone density, brain anatomy and function, the experience of pain, the response to infection, and ultimately, the timing and causes of death.

“All over the world, people who are looking for differences between men and women are finding them,” says Legato.

But there is still much we do not know. The task today is to explore the implications of these data and apply it—to clinical practice, to policy decisions, and to public health. “The current period of evolution in women’s health has provided us with many answers, but new and difficult questions persist,” says Paula Johnson, MD, MPH, a practicing cardiologist and executive director of the Mary Horrigan Connors Center for Women’s Health and Gender Biology, at Brigham and Women’s Hospital, and an associate professor of medicine at Harvard Medical School.

Dr. Paula Johnson: Would like to see the field of women’s health begin to consider women in the broader social and economic context of their lives.

For instance, why are women more susceptible to the adverse effects of cigarette smoking than men? Why does diabetes appear to more negatively impact women’s hearts than men’s? And why are women more likely than men to recover language ability after suffering a left-hemisphere stroke?

But the central inquiry that underlies them all, and the one that drives Johnson’s and Legato’s efforts is this: Why is women’s health important and how is it relevant to the health of the human race?

Sex- and Gender-Specific Medicine
Despite all the advances that have been made in the field of women’s health, many practicing physicians still hold the “bikini view” of women’s health—that is, that it equals breast and reproductive health. Both Johnson and Legato believe it’s time to broaden this view.

The first and necessary step is to  advance medical research by increasing the number of female participants. Historically, women have been excluded from direct clinical investigations out of a protectionist concern for their reproductive health. This arguably noble action, however, carries a price.  Excluding women, or any group of people, from research adds to the gaps in what is known about those groups. And this increases the disparities in their care.

Legato emphasizes that if women as well as men are going to benefit from medical research, then they need to assume some of the risks. Unfortunately, this is not a simple matter of inclusion. In order to convince more young women to participate in studies, investigators need be able to answer them truthfully when they ask questions about the potential effects on their reproductive competence, or on their fetus, should theyconceive a child in the course of the clinical trial. Often, “no one knows the answers to those questions,” says Legato.

Many practicing physicians still hold the “bikini view” of women’s health—that is, that it equals breast and reproductive health.

Such questions, notes Johnson, are “very appropriate.” But she adds that a larger issue is at stake. That is, should the biological fact that women bear children be a major barrier to understanding women’s unique biology in every organ system, therefore inhibiting our ability to achieve the best health possible for women? Legato contends that the answer is “a resounding no.”

Clinical trials are just the beginning. Both Johnson and Legato assert that the entire concept of women’s health needs to be expanded. In their view, women’s health needs to encompass differences in both sex and gender.  

This idea was brought into the spotlight in 2001, in a seminal report published by the Institute of Medicine entitled, “Exploring the Biological Contributions to Human Health: Does Sex Matter?”

The report draws a clear distinction between sex and gender and explains in detail how the concepts apply to understanding of human health and disease. It defines sex as “the classification of living things as male or female according to their reproductive organs and functions assigned by chromosomal complement.” Gender, it explains, is “a person’s self-representation as male or female, or how that person is responded to by social institutions based on the individual’s gender presentation.” In other words, sex is a biological construct, gender a social one.

The report also opened a door to further investigation with its conclusion that not only does sex matter, but it matters “in ways we did not expect and in ways we have not begun to imagine.”

To Legato, that monograph demonstrated how quickly and dramatically the Institute’s thinking had changed since 1994, the year it first entertained the possibility that men and women experience disease differently. In addition, she says, the report legitimized her interest in transforming women’s health into a field that examines both the normal function of males and females and their different experience of the same diseases.

What lessons from women’s health can be applied to help men dealing with, for example, prostate cancer or diabetes?

Three years ago, she summarized many of these differences in two books, Eve’s Rib, written for laypeople, and The Principles of Gender Specific Medicine, the first textbook on the subject for physicians. Today, she says, it’s time to take that same focus and apply it to men. And among her latest ambitions is to investigate the vulnerabilities inherent in men’s genetic and hormonal makeup and think about how to correct them, something she says “we really haven’t done yet.” Instead of drilling down into individual variations, “we’ve assumed that all men are the same, the way we’ve assumed that all women are the same as men.”

A growing body of knowledge
Here we are, approaching 2007. What has changed? Legato points out that in the past few years there have been several important scientific breakthroughs supporting gender-medicine, much of it taking place in the field of human genetics.

It began with the mapping of the human genome, which raises a new set of questions, not just about sex and gender, but about how investigations are conducted.

More recently, researchers at the University of California at Los Angeles demonstrated 25,281 differences in gene expression between male and female mice. Their findings were published in the July 2006 issue of Genome Research. Legato says she is intrigued by the implications of these differences, “not just for the preservation of health, longevity, and the quality of life, but for the prevention, detection, and treatment of illness.”

She points to another noteworthy study published in the June 10, 2005 issue of the journal Science, by Michael Mendelsohn and his colleague Richard Karas of the Molecular Cardiology Research Institute at Tufts-New England Medical Center in Boston. Their research explores, in detail, the molecular and cellular basis of cardiovascular gender differences.

At the Foundation for Gender-Specific Medicine, Legato and her colleagues are incorporating some of the most recent findings into position papers on the gender-specific treatment diseases such as diabetes and cardiovascular disease. She hopes the guidelines will be applied at academic centers for sex/gender-specific medicine, such as the Partnership for Gender-Specific Medicine at Columbia. She adds that she’d like to see centers such as these spread, the way women’s health centers once did, and to demonstrate whether the practice of gender medicine influences patient outcomes

A model of integration
The Connors Center at Brigham and Women’s Hospital is one center that is incorporating women’s health into all aspects of medicine—today. With regard to research, the center conducts a robust program in sex- and gender-based biology that aims to bridge the gap between what we know (observational data) and what we don’t (the biological underpinnings of disease).

We know, for example, that coronary disease may develop differently in some women, and that some young women develop ischemia without the discreet blockages, or stenoses, commonly found in men. It is suspected that these women develop a longer narrowing spread more evenly throughout the blood vessel. But we don’t know why this happens. Investigators at the Connors Center are studying the hormone and gene interactions that may one day explain this finding and others, and lead to new strategies for prevention and treatment.

The investigators are also looking into why autoimmune diseases and depression are more common in women than men; why women appear to be more susceptible to the adverse effects of cigarette smoking; why having a high level of HDL (good cholesterol) is more important in women than men; and why women with diabetes are more likely to die of cardiovascular complications than are men with diabetes.

In addition to funding original research, the hospital is applying the results of that research—and research from around the world—to new models of care for women throughout Brigham and Women’s Hospital. And in the Gretchen S. and Edward A. Fish Center for Women’s Health, part of the Connors Center, investigators are creating a “learning laboratory” in which they measure outcomes and generate new questions to be researched. The goal, Johnson says, is to discover how to more routinely provide gender-specific care that incorporates science and addresses the needs of patients within the context of their lives.

At the same time, the Connors Center is bridging another gap—the one between medicine and public policy. Johnson believes that physicians can, and should, become public policy advisors, as they are the most intimately familiar with the latest research and relevant patient issues. Today, she and her colleagues are working to make sure women’s health issues are considered in the drafting of Massachusetts’ new health care legislation and stem cell legislation, among other initiatives.

Dr. Paula Johnson sees opportunity to “think more strategically and create systems that are not just focused on the acute intervention . . . but that support women’s overall health and also their vibrant role in the community.”

And because, as Johnson points out, women’s health around the world is a driver of health care and the economy, it is important to cross geographical boundaries, in addition to intellectual ones. “We have the ability to not make the mistakes we’ve made in our own health care system,” she notes, referring to the U.S. “medicalized” model which focuses on providing medication rather than improving the wellbeing of women and society. She sees an opportunity in the next five years to “think more strategically and create systems that are not just focused on the acute intervention—whether it is HIV/AIDS, childbirth, or malaria—but that support women’s overall health and also their vibrant role in the community.” Organizations such as Physicians for Human Rights, the Harvard Humanitarian Initiative, and many other non-governmental organizations have already begun such efforts.

Last, new models of training in research are needed so that tomorrow’s investigators learn to make sex- and gender-based science part of what they think about routinely. “They need to be trained in an interdisciplinary model, one that is not only translational but one that gets them to think about the social context of women’s health, which frequently impacts their biology,” says Johnson. To this end, two dozen centers, including the Connors Center, have been established to foster women's health research with an emphasis on mentored, interdisciplinary collaboration across a variety of disciplines as part of the “Building Interdisciplinary Research Careers in Women’s Health” program, supported by the National Institutes of Health.

We’ve come a long way since women’s health was a one-system silo, to be sure. But we have a very long way to go. “We are only at the tip of the iceberg in understanding sex-related differences in health and disease, most specifically, in women,” says Johnson. “The challenge is to not only develop better diagnostic tools but to better understand the interaction of hormones and genes in order to understand the underlying causes of disease in order to develop the best strategies for prevention and treatment.”

In other words, “We are only at the beginning of our journey.”

Copyright 2006 Harvard Medical International