A distinct science

NO one needs a biology class to be persuaded of a profound fact of life: Men and women are different.

Yet until relatively recently, the scientific world didn’t seem to fully appreciate that fact. For many years, most doctors believed the differences between men and women were restricted to gynecology and urology. The world of women’s health focused on childbearing and then on menopause. For virtually all other diseases and disorders, whatever happened to a man, it was thought, also happened to a woman.

As it turns out, the biological truth is vastly different. “Women aren’t just small men with different plumbing and hormone problems,” says Sherry Marts, a vice president of the Society for Women’s Health Research. “Basically there are differences pretty much everywhere people have looked, in all the physiological systems of the body.”

Why, for example, are women 2.7 times more likely to suffer from autoimmune diseases such as lupus, fibromyalgia and multiple sclerosis? Why, after a left-hemisphere stroke, are women able to recapture their language ability more easily than men? Why are some cancers less fatal for women, while others are more so? Why are women more sensitive to pain than men? And in one of the most studied questions, why do women with heart disease have very different symptoms from men?

Burgeoning research in cardiovascular disease, the central nervous system and perception of pain, in the immune system and the field of autoimmune disorders, has revealed fundamental differences between the sexes in their vulnerability and experience of these conditions. The recent mapping of the X chromosome promises to help scientists understand the intricacies of that chromosome and of human health, as well as more than 300 genetically linked diseases. And ongoing results from two large studies of women -- the Nurses Health Study, a nearly 30-year-long project involving about 122,000 nurses, and the Women’s Health Initiative, with more than 160,000 participants in several clinical trials -- provide a trove of scientific research.

Marcia Stefanic, a professor of medicine at Stanford University and chairwoman of the steering committee of the Women’s Health Initiative, says the results of these studies could benefit men as much as women. “Sex and age matters,” she says. “We are realizing that some diseases, such as heart disease, affect men at a younger age, and women when they are older. While others like osteoporosis affect women at a younger age, but is increasingly a problem for men as they grow older. Eventually, we will be able to help both men and women as we understand their different vulnerabilities.”

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Defining the terms

Although the terms “sex” and “gender” often are used interchangeably, they have crucial distinctions. According to a 2001 Institute of Medicine report, sex “is the classification of living things generally as male or female according to their reproductive organs” and the way that the X and Y chromosomes are organized.

Gender, on the other hand, involves a person’s self-image and “how that person is responded to by social institutions” based on the way the person presents him or herself. Gender is of course “rooted in biology and shaped by environment and experience.” In some ways, sex and gender go to the heart of the nature versus nurture debate.

“Both have a huge impact on an individual’s biology and how aggressively we treat disease,” says Dr. Barbara Ann Gilchrest, a Boston University dermatologist involved in the IOM study. Heart disease, the leading cause of death in women, illustrates both the sex and gender complications.

When Dr. Bernadine Healy was president of the American Heart Assn. in 1988, she was determined to focus on women and heart disease during her tenure. Healy, a cardiologist who formerly headed the National Institutes of Health, encountered “tremendous resistance” when she tried to get the group to focus on that issue. “Heart disease was such an egregious example of trying to put women outside of medical research.” she says. Eventually, her efforts “took off like wildfire in the organization.”

Such thinking is reflected in a 1995 Gallup survey that found that nearly nine of 10 internists surveyed said the signs and symptoms of heart disease were the same for men as for women. Nearly a third of the 300 doctors surveyed said they did not know that coronary artery disease was the leading cause of death in women.

Although public education campaigns during the last 10 years aimed to heighten awareness of the issue, a 2004 survey by the American Heart Assn. found that 38% of women reported their physicians had never discussed heart disease with them.

Moreover, women of all ages were less likely to receive blood-thinning drugs and beta blockers in the first 24 hours following a heart attack. Considering such lack of guidance from some doctors, it is not surprising that many women remain unaware of their heart disease risk.

When Lynne Whalen, a real estate attorney in Monrovia, had a fibroid tumor removed in 1997, the anesthesiologist ordered a routine EKG before her surgery. When Whalen woke up after her fibroid procedure, the doctor told her the EKG results showed a problem with her heart.

At the cardiologist’s office, Whalen, 52, a former smoker who came from a long-lived family with no history of heart disease, felt out of place. “There were all these old men and women in the waiting room -- the women were all older than the men.” Subsequent tests showed that one crucial artery was 80% to 90% blocked. The doctor told her she was at imminent risk of a heart attack or stroke and needed an angioplasty. During her surgery, the doctors put in place a stent -- a small mesh tube that widens the artery and keeps it clean. For many women with heart disease, there are no warning signs, no pain, no discomfort. Whalen, however, had only recently quit smoking after a nearly 30-year habit. When her internist earlier that year ordered a cholesterol test, the result was a respectable 210. What Whalen found out later though was that her HDL-LDL ratio (the “good” and “bad” cholesterol ratio) was out of whack; her LDL, the bad cholesterol, was at 300.

Whalen’s experience helps illustrate the complex biological differences between men’s and women’s hearts.

Women are more likely than men to develop what is called “left ventricular hypertrophy,” which means that their heart muscle gets enlarged, thickened and shortened over time, typically a result of high blood pressure, hardening of the arteries and obesity. The result is that some women’s hearts are less able to meet the pumping demands of normal circulation. With heart vessels that are, on average, 10% smaller than men’s, those demands can further weaken heart muscles.

Women have a lower rate of heart disease than men, and estrogen was once thought to have a lot to do with that; especially because when women suffered from heart disease it typically occurred long after menopause. Estrogen seemed to have protective effects in the heart and it even lowered the level of bad cholesterol in the body while raising the level of good cholesterol. But estrogen therapy after menopause is not only not protective -- it increases the risk of heart attacks and strokes.

The Women’s Health Initiative even halted the estrogen therapy trial early because of the dangers. One lingering question, however, is when to begin estrogen therapy.

“It seems that if you start post-menopausal hormone therapy early enough, estrogen may protect the heart and the blood vessels,” says Dr. JoAnn Manson, chief of preventive medicine at Brigham and Women’s Hospital in Boston. “But if you start estrogen late, and there is already advanced arterial sclerosis, then estrogen is more likely to cause problems.”

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Uncovering genes’ secrets

Women’s health differences go far beyond hormones. Potentially, some explanation will be found at the most fundamental level of human biology: the chromosome. The lesson from freshman biology -- women are women because they have two X chromosomes, and men are men because they have an X and a Y chromosome -- was underscored in March, when an international team of scientists presented its findings from mapping the X chromosome, with its 1,098 genes.

More than 300 X chromosome-linked genes are associated with diseases passed from mothers to sons, and the recent findings may help reveal why that happens. Other genes may unlock some of the more intricate secrets of women’s health and response to illness.

Scientists once believed that one of the X chromosomes was relatively passive in relation to the other. New research has shown that there is enormous variation in the interactions between the two X chromosomes in women. Some of the genes are turned on, others are turned off. And scientists are only beginning to look at what these implications might be.

This genetic on-off switch, says UC San Francisco pediatrician Melvin Grumbach, could reveal some of the ways that genes “play a role in the differences between men and women around autoimmune diseases. Some of these differences are clearly related to genetic differences between males and females, and the X chromosome has something to do with that.”

Discovering the various secrets of the X chromosome may explain what already has been observed in women’s health.

For example, functional magnetic imaging of women’s brains after strokes have revealed that one reason women recover the use of language after a stroke in their left hemisphere is because women’s language centers appear to exist on both sides of the brain, whereas in men, they are concentrated on the left side.

But why does this difference in brains exist at all? The answer to this question, and to the questions of the susceptibility of women to lung cancer, to increased sensitivity to pain, even to certain medicines, may well be revealed as the X chromosome is more fully explored.

From chromosomes to cells, from hearts to brains, from livers to intestines and from skin to blood, the vast and fascinating realms -- and the elegant details -- of the differences between the two sexes are slowly being understood.

And the goal is both exquisitely modest and wildly ambitious: To truly understand all the aspects of health in a single human being.

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A look at the research

Do women react differently to health challenges? The one-word answer: Definitely. The Society for Women’s Health Research (www.womenshealthresearch.org) collected some of the research in a number of diseases and disorders, including:

Autoimmune diseases

* Women are 2.7 times more likely than men to acquire an autoimmune disease.

* Almost three-fourths of those who suffer from rheumatoid arthritis, multiple sclerosis and myasthenia gravis are women.

* Lupus affects nine times as many women as men.

* Twice as many women as men suffer from multiple sclerosis.

* About 90% of all people with fibromyalgia are women.

Cancer

* Women are less likely than men to die of cancer of the head and neck, esophagus, stomach, liver, or pancreas; women with bladder cancer are more likely to die from the disease than men.

* Lung cancer is the leading cause of cancer death in American women, and more women will die of lung cancer this year than breast, cervical, ovarian and skin cancers combined.

* Although colorectal cancer risk is similar for men and women, men are more likely to be screened for it.

* Among young cancer patients, women are more likely to survive; among older patients, men are more likely to survive.

Cardiovascular diseases

* Heart disease is the leading killer of U.S. women.

* Women represent 54% of all deaths from cardiovascular disease.

* Women represent 61% of total stroke deaths.

* Forty percent of women who have cardiac arrest report having stress, such as divorce or depression, before the event, contrasted with 16% of men.

* Only 5% of women report that they physically exerted themselves right before experiencing a heart attack; the comparable figure among men is 40%.

Diabetes

* Approximately 9% of U.S. women have diabetes, but about one-third of them do not know it.

* Diabetes is at least two to four times more prevalent among African American, Latino, American Indian and Asian/Pacific Islander women than among white women.

* The risk of diabetic coma is higher among women than men, but the amputation rate is lower.

HIV/AIDS

* The physical decline of women with HIV is more rapid than for men with the infection.

* Women with HIV are more likely than men to experience significant drops in their body weight, which can lead to wasting syndrome.

Mental health

* After puberty and continuing throughout their lives, women are more likely than men to suffer from depression.

* Women have a higher risk of developing Alzheimer’s disease than men.

* The risk for post-traumatic stress disorder following a traumatic event is two times higher in women than men.

-- Marianne Szegedy-Maszak