Inferior: How Science Got Women Wrong—and the New Research That's Rewriting the Story

by Angela Saini

If a phenomenon affects women and only women, it’s all too often misunderstood. And this is compounded by the fact that even though they’re good at surviving, women aren’t healthier than men. In fact, quite the opposite.

“If you could add up all the pain in the world, all the physical pain, I suspect that women have way, way more of it. This is one of the penalties of being a better survivor. You survive, but maybe not quite as intact as you were before,” says Steven Austad. Statistically, it could even explain why women seem proportionally sicker than men. “Part of the reason that there are more women than men around in ill health is to do with the fact that women have survived events that would kill men, and so the equivalent men are no longer with us.”

This isn’t to say autoimmune disease is always hardest on women. When men develop multiple sclerosis, they tend to get it worse. Women also survive with it longer than men do. Even so, of the roughly 8 percent of Americans who suffer from autoimmune diseases, estimates suggest that at least three-quarters are women.

When estrogen and progesterone levels drop through the years following the start of menopause, a woman’s immunity advantage starts to drop away as well.

Research on influenza by Sabra Klein, an immunologist at the Johns Hopkins Bloomberg School of Public Health, has shown that while women are generally hit by fewer viruses during an infection, they tend to suffer more severe flu symptoms than men do. She reasons that this may be because women’s immune systems mount sturdier counterattacks to viruses, but then suffer when the effects of these counterattacks upset their own bodies.

Part of this is due to autoimmune diseases that affect the joints, such as arthritis. The physical toll of childbearing and the hormonal changes of menopause may also leave women with more physical problems and disabilities, especially in later life.

But the overall picture of pain and ill health is complicated. “Crossculturally women just report more physical limitations and more disabilities. It’s really widespread,” says Austad. When it comes to biological clues about the underlying reasons for this sex difference in disease or survival, however, he adds, “I don’t feel very confident of any explanation.”

Society and the environment can sometimes affect illness more than a person’s underlying biology. “Women are less likely to go to the hospital when they’re feeling chest pain than men,” explains Sandberg, who has looked at gender differences in heart disease in particular. Men’s and women’s health habits throughout the world differ in countless other ways.

Not only a woman’s own behavior but that of others around her can also affect her health. From the second a girl is born, she’s placed in a different box. She may be handled differently, fed differently, and treated differently. This marks the beginning of a lifetime of differences in the way doctors and medical researchers approach her as well.

In 2015 a team of British researchers studying cancer diagnosis in the United Kingdom found that for six of the cancers that affect both men and women, including bladder and lung, it took longer for women to be diagnosed after going to doctors with their symptoms. For gastric cancer, a woman waited on average a full two weeks longer for a diagnosis.

For males with XY sex chromosomes, however, a matching allele isn’t always there. X and Y don’t have the same genes in the same locations. In fact, the Y is far smaller than the X.

“It’s long been thought, and there is good evidence for this, that having two versions of the gene buffers women against certain diseases or environmental changes,” says Arnold.

If a man happens to have a genetic mutation on one of his X chromosomes that causes an illness or disability, he has no way of avoiding it. A woman, on the other hand, will have an extra X chromosome to counteract it, unless she’s unlucky enough to have the same genetic mutation on both X chromosomes, one from each parent.

Men are more susceptible to some well-known genetic traits simply because they have one X chromosome. They’re known as “X-linked disorders.” They include red-green color blindness, hemophilia, muscular dystrophy, and IPEX syndrome, which affects immune function. Mental retardation, which affects 2 to 3 percent of people in developed countries and significantly more men than women, also has a strong link to the X chromosome.

"Retardation" isn't still the technical term is it?

“What we know of X-linked diseases is that they’re pretty rare,” says biologist Steven Austad. “But I think there are a lot more X-linked diseases than we think about. . . . This probably underlies a considerable proportion of the sex difference.”

One example is respiratory syncytial virus, which infects the lungs and breathing passages and is one of the biggest causes of bronchitis in children under the age of one in Britain and the United States. Researchers have found that the virus tends to hit boys far more than girls, and that something inside one particular gene on the X chromosome might be responsible.

In 1961 English geneticist Mary Frances Lyon found that, even though women have two X chromosomes, one is randomly inactivated in every cell.

Women are therefore a genetic mosaic in which some cells have genes from one X chromosome, and other cells have genes from the other. Researchers have more recently discovered that some genes on the second X chromosome aren’t actually inactivated at all.

In 2009 researchers at Penn State College of Medicine totted up these uninactivated genes to discover that these islands comprise 15 percent of genes on the second X.

The problem for all researchers in this area is that it’s not easy to distill the impact of the X chromosome from all the other factors that also cause a person to get sick or die. Most diseases don’t appear to be linked to one or even a few genes in the way that X-linked genetic disorders such as hemophilia and muscular dystrophy are.

Since sex hormones before birth have the most obvious impact on male and female bodies (without androgens, a male wouldn’t develop male gonads, for instance), researchers have created laboratory mice for Arnold that don’t produce these hormones. The resulting mice have XY chromosomes, like a male, but also ovaries, like a female.

When he and his team looked at body weight, they found that mice get fat if their gonads are removed. But animals with two X chromosomes get a lot fatter than those with just one. It mirrors something we see in human adults—women tend to have a higher percentage of fat mass in their bodies than men.

Their take-home message is that many of the sex differences we see in health are rooted deep down in genetics.

Richardson warns against this focus on genetics as an umbrella explanation for sex difference because of how it blurs away the effects of society and culture, as well as other biological factors. Age, weight, and race, for example, are known to have a huge impact on health. Hormones are important, too. She notes that the body of genetic evidence when it comes to sex differences paints an overwhelming picture of similarity.

“I one time looked into the rodent literature on dietary restrictions,” recounts Austad. “There are hundreds and hundreds of studies. And I found that there was only a handful that included both sexes. . . . People seem to be willing to extrapolate from one sex and just assume that everything they find is going to be true in the other sex.”

Of the ten scientific fields they investigated, eight showed a male bias. In pharmacology, the study of medical drugs, the articles reporting only on males outnumbered those reporting only on females by five to one. In physiology, which explores how our bodies work, it was almost four to one.

In research on the evolution of genitals (parts of the body we know for certain are different between the sexes), scientists have also leaned toward males.

In 2014 biologists at Humboldt University in Berlin and Macquarie University in Sydney analyzed more than three hundred papers published between 1989 and 2013 that covered the evolution of genitalia. They found almost half looked only at the males of the species, while just 8 percent looked only at females. One reporter described it as “the case of the missing vaginas.”

Until around 1990, it was common for medical trials to be carried out almost exclusively on men.

“You don’t want to give the experimental drug to a pregnant woman, and you don’t want to give the experimental drug to a woman who doesn’t know she’s pregnant but actually is,” explains Arthur Arnold. The terrible legacy of women being given thalidomide for morning sickness in the 1950s proved to scientists how careful they need to be before giving drugs to expectant mothers.

A woman’s fluctuating hormone levels might also affect how she responds to a drug. Men’s hormone levels are more consistent. “It is much cheaper to study one sex. So if you’re going to choose one sex, most people avoid females because they have these messy hormones. . . . So people migrate to the study of males. In some disciplines it really is an embarrassing male bias,” he adds.

A 2010 book on the progress in tackling women’s health problems, cowritten by the Committee on Women’s Health Research that advises the National Institutes of Health (NIH), notes that autoimmune diseases—which affect far more women than men—remain less well understood than some other conditions.

Another problem is that women may respond differently from men to certain drugs. Medical researchers in the mid-twentieth century often assumed this couldn’t be a problem.

In 2000 the US Government Accountability Office looked at the ten prescription drugs withdrawn from the market since 1997 by the US Food and Drug Administration. Studying reported cases of adverse effects, it found that eight drugs posed greater health risks to women than to men. The withdrawn drugs included two appetite suppressants, two antihistamines, and one for diabetes.

Again, though, this line of thinking risks drawing divisions between women and men when the picture of disease is far more complicated. While there’s a clear benefit to better understanding women’s bodies and having drugs that suit both sexes, the emphasis on sex difference starts to make it seem as though women’s bodies are from Venus and men’s bodies are from Mars.

In 2002 researchers at Yale University School of Medicine decided to take a look at the data around digoxin, analyzing its effects by sex. Between 1991 and 1996, researchers had carried out randomized trials on heart patients using digoxin. They found that it didn’t affect how long a patient lived, but it did on average reduce their risk of hospitalization. But the Yale team noted that the drug was tested on roughly four times as many men as women, and they didn’t respond identically.

The Yale University result later turned out to be not what it seemed. More recent studies, including one with a much larger sample group published in the British Medical Journal in 2012, have suggested that in fact there isn’t a substantially increased risk of death for women from digoxin use at all.

Around sixty million sleeping pills were prescribed in the United States in 2011, up from forty-seven million just five years earlier, according to data collected by the health-care intelligence company IMS Health.

The effects of zolpidem can also last longer than one night, leading to drowsiness the following day, which can in some cases make it dangerous to drive. Long after it was approved for market, research emerged that women given the same dose as men were more likely to suffer morning drowsiness. Eight hours after taking zolpidem, 15 percent of women but only 3 percent of men had enough of the drug in their system to raise their risk of a driving accident.

However, just as with digoxin, the finding needed to be unpacked a little further. In 2014 research exploring the effects of zolpidem, carried out by scientists at Tufts University School of Medicine, suggested that its lingering effect may be mostly due to women’s lower average body weight compared to men, which means the drug clears from their systems more slowly.

Besides average body weight and height, women also have on average a higher percentage of body fat than men. And they generally take longer to pass food through their bowels. Both are things that might affect how drugs behave in their bodies.

What also counts is the experience of being a woman, socially, culturally, and environmentally. “Both sex and gender are important factors for health,” reminds Janine Clayton. Ideally, then, people should be treated according to the spectrum of factors that set them apart. Not just sex, but also social difference, culture, income, age, and others.

Understanding why women tend to live longer could help men live longer. Including pregnant women in research may open up the cabinet of drugs that doctors can’t currently prescribe because their effects on fetuses are uncertain.

In 1993 the US Congress introduced the National Institutes of Health Revitalization Act, which includes a general requirement for all NIH-funded clinical studies to include women as test subjects, unless they have a good reason not to. By 2014, according to a report in Nature by Janine Clayton, just over half of clinical-research participants funded by the NIH were women.

Research into sex differences has an ugly and dangerous history. As the examples of digoxin and zolpidem prove, it’s still prone to errors and overspeculation. As much as it can improve understanding, it also has the potential to damage the way we see women and drive the sexes farther apart.

Cute though babies are, studying them this way is not as much fun as it might seem. It’s almost like working with animals. The challenge is to come up with clever experiments that get to the heart of their behavior without accidentally reading too much into what an infant does.

Gliga’s work focuses on how children develop in their early years, in the tradition of the Swiss psychologist Jean Piaget who, from the early twentieth century, observed his own children and famously realized that many of the assumptions scientists had made about early development were wrong.

We know that around the age of two or three, children start to become aware of their own sex. Between the ages of four and six, a boy will realize that he will grow up to be a man and a girl that she will be a woman. It’s also by then that children have some understanding of what’s appropriate for each gender according to the culture they’re in.

Researchers like those at Birkbeck College have realized that one of the most effective ways for scientists to sift nature from nurture, the biological from the social, is by studying children so young that they haven’t yet been exposed to society’s heavily gendered ways.

Harvard University cognitive scientist Steven Pinker and London School of Economics philosopher Helena Cronin have both deployed it to argue that innate differences between the sexes exist.

Ugh Pinker