Amid the shortage of swine flu vaccine last fall, a Johns Hopkins immunology expert proposed a surprisingly simple-sounding fix: Give women a smaller dose than men so there would be more to go around.

Because women's bodies have been shown to generate a stronger antibody response than men's, the argument went, a smaller dose would be enough.

The proposal - made in a New York Times opinion article - was so well-received that the World Health Organization asked Sabra Klein of Hopkins' Bloomberg School of Public Health to draft a paper on it. But so far as Klein knows, no one has put the proposal into widespread clinical practice.

"One physician wrote me to say he felt comfortable giving his wife half a dose," said Klein, an assistant professor in molecular microbiology and immunology.

A rapidly growing body of research shows men and women are biologically different in ways that have nothing to do with the obvious physical features and lots to do with which diseases strike and how successfully or not the body fights them off. Differences in metabolism, brain structure and chemistry, lung development, hormones and chromosomes might affect such things as how well medicines work, whether patients recover language after a stroke and, possibly, how many cigarettes it takes to kill them.

But for the most part, the idea that males and females are very different patients hasn't made its way into the doctor's office.

"We really do often strive for this one-size-fits-all in medicine," said Klein. "Our biology is different. Whether you're talking about responses to pain or chemotherapy, it can result in differences in how we respond to treatment. ... There needs to be a better appreciation of these differences."

Only in recent decades have researchers come to suspect that basic biological differences might account for such things as why autism is four times more common in males or why lupus and irritable bowel syndrome predominantly afflict females.

"Until recently, women were often excluded from pharmaceutical studies," said John Vandenbergh, a retired North Carolina State University biology professor who participated in a landmark study of sex differences. "That was done on purpose ... and [the] reason was, it may affect fetal development. 'Why don't we do just males?' That all made sense until we realized males and females are truly different."

Since 1993, federally funded research and drug trials have been required by law to include women. But even today, researchers and drug and medical-device companies do not always break out the results of their studies by sex. That can mean missing red flags before a drug or device goes on the market, said Florence Haseltine, a reproductive endocrinologist who in 1990 formed the Society for Women's Health Research.

"When you give medications, often one sex - if it's going to have bad side effects - is the canary in the coal mine," Haseltine said. She noted the antihistamine Seldane was pulled off the market in 1998 after women taking it experienced cardiac arrhythmia.

Sex-based information is also lacking when it comes to public health data. Klein, the Hopkins researcher, has been frustrated that swine flu data is not consistently broken down by patients' sex. What sex-based information is out there - Canada and the state of California made note of it - indicates that the H1N1 virus strikes women particularly hard; about 70 percent of flu patients requiring hospitalization last year were women, data from Canada and California show.Statistically, Klein said, there does seem to be something about swine flu vulnerability and being female. But it's difficult to study that, she said, when most states do not report swine flu cases by sex. Despite those lapses, more attention has been paid to sex differences in the past decade, in large part because of a book-length 2001 report by the Institute of Medicine, "Exploring the Biological Contributions to Human Health: Does Sex Matter?"

"Up until the point of the IOM report, people always thought that women and men were basically the same, except for the hormones," said Dr. Michael Lockshin, a rheumatologist and Cornell Medical College professor who participated in the report. "In fact, there's pretty profound differences in biology between the sexes, and that biology may have relevance to most of what we talk about in human disease."

The report's findings have been slow to trickle into medical research, he said.

"At the time the IOM book was done, I used to raise my hand - in New York, we interrupt speakers at forums - and the speaker would say, 'Uh-oh, you're going to ask me that sex question again.' I got to be known as a gadfly on that. But what's happening now, I don't have to ask the question. The speaker is getting to it on his own."

But there is a long way to go, he said. Lockshin, who serves as editor of the medical journal Arthritis & Rheumatism, sometimes still has to "nudge" researchers submitting articles to the publication to break down their findings by sex. He doesn't have to nudge as hard as he used to, but he would like more detail. Of the women included in a research study, how many are post-menopausal? How many pregnancies have they had? "Those are things that are almost never considered by anybody," he said.

In most basic research, scientists still do not know the sex of the tissue cultures they work with, Lockshin said. And researchers working with lab animals usually stick with one sex or the other. Some prefer female rats because they don't bite. Others use male rats because researchers do not want to have to account for monthly hormonal cycles - no matter that half the human population whom the research is ultimately meant to serve happens to cycle, too.

Because 90 percent of lupus patients are female, lupus researchers use female rats, Lockshin noted. He wonders: Are researchers missing something that could help male lupus patients?

Sex-based research has resulted in some clinical applications, such as a knee implant with a narrower profile and different angle, developed a couple of years ago for women. It's been known for many years that women suffering heart attacks can experience severe neck and back pain instead of the crushing chest pain that men have. While women's heart attacks sometimes still are misdiagnosed, word about that sex difference has at least gotten out - most recently in a public service announcement aired during the Super Bowl.

Some of the sex differences that researchers are finding are compelling but not yet at the stage where they're clinically useful.

"Lung cancer susceptibility is probably different for women than men," said Dr. Julie Brahmer, a lung cancer expert at the Johns Hopkins Kimmel Cancer Center. The theory, still considered controversial, might have to do with differences in the way women metabolize nicotine or the fact that girls' lungs mature in their teens, while boys' continue growing into their 20s. At the same time, women who get lung cancer tend to do better with treatment than men.

"We're trying to figure out why that is," Brahmer said. "Do we metabolize the chemotherapy drugs differently?"

Even these unanswered questions can serve a purpose. Jo Parrish, vice president of the Society for Women's Health Research, likes to pop this one whenever a doctor scribbles out a prescription for her: "Was this drug tested on women?"

"And they really have no clue," she said. "Even if they don't know, the very fact that you asked the question is making the physician think about it."

The study of sex differences grew out of the women's health movement, which in the early 1990s was pushing for equal funding for diseases like breast cancer that predominantly afflict women. It wasn't an entirely smooth transition from "Equity Now!" to vive la difference.

Haseltine, the Society for Women's Health Research founder, recalled a friend's reaction when Yale researchers Bennett and Sally Shaywitz found in 1995 that men and women process language differently. The friend was Eleanor Smeal, the Feminist Majority Foundation president.

"It was really not what she wanted to hear," said Haseltine. "I said, 'Eleanor, we've got a problem because this is only the beginning. You have to understand the arguments. Different doesn't mean better or worse. It just means different.' "

When Hopkins' Klein proposed giving women a half-dose of the H1N1 vaccine, she braced for a similar backlash.

"I was sort of waiting for some groups to possibly say something like, 'Women are getting slighted,' " she said.

But the idea was accepted positively - if not clinically.

Before most doctors start giving women a smaller dose of the flu vaccine, Klein said, the World Health Organization and the Centers for Disease Control will probably have to get behind the idea. She believes that could happen, given that the WHO has asked for a paper on the subject. "There's research out there," she said. "It's out in the literature, but it's not sitting in a reference book on somebody's desk."