The sleeping tablet Ambien is a blockbuster – it’s one of the most commonly used insomnia and jet lag treatments in the world. Yet a decade or so after its approval in 1992, worrying reports began to emerge. Users – particularly women – were behaving bizarrely after taking the sedative, then having no recollection of what they’d done. There were accounts of people being involved in driving accidents the morning after taking the tablets.
Research confirmed that women were more likely than men to have bad side effects after taking Ambien. Then, in 2013, US drug regulators confirmed there was a problem: the manufacturer’s recommended dose was double what it should be for women. The research leading up to the drug’s launch had not separated out men and women, so it had taken two decades of public use to recognise that women metabolised Ambien at a significantly slower rate than men. The result was that when they woke up, they still had the drug in their system, leaving them drowsy, confused and liable to have a car crash.
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If it seems odd that the possibility of different drug doses for women wasn’t considered as a matter of course 25 years ago, then it’s remarkable that this is still the case. Only in the past decade has the idea that women may need different treatments from men gained a foothold in mainstream medicine. Far from being a minority feminist movement riding the wave of #MeToo awareness, the new field of gender medicine is rebuilding medicine from the foundations of sound science. In the process, it may transform men’s health too.
Medicine has long worked on the assumption that women are essentially men with boobs and tubes – and so ‘women’s health’ became a term associated with the reproductive organs. It was only at the dawn of the 21st Century, with the emergence of evidence that women were experiencing heart attacks entirely differently from men, that the old ‘bikini medicine’ outlook began to be seriously challenged.
Heart researchers found that all those supposedly ‘classic’ symptoms – a tight pain in the chest, shooting pains down the arm, dizziness – were actually male symptoms. Women experience other signs such as shortness of breath, fatigue, nausea, and pain in the jaw or back. Yet these symptoms, which may be down to different patterns of obstruction in women’s coronary arteries, were not in the research literature, and were not being recognised by doctors. Women were dying of heart attacks as a result.
In the two decades since, a cascade of evidence has emerged indicating the deep-seated differences in male and female biology, and the need for different approaches to diagnosis and treatment.
For example, women have a faster and stronger immune response than men (so men are significantly more likely to die of infectious diseases), but women are more likely to have autoimmune diseases such as rheumatoid arthritis. Women’s and men’s metabolism, experiences of pain, and likelihood of developing Alzheimer’s disease are all different.
Here, it’s worth pointing out that sex and gender have different meanings, but are closely linked. ‘Sex’ refers to the biological differences between males and females. ‘Gender’ refers to a person’s characteristics or identity as shaped by society and the environment as well as biology. Gender medicine embraces both meanings, considering how women’s environment also affects their health and the way they are treated.
The differences between the sexes begin before birth, with male and female sex hormones such as testosterone and oestrogen helping mould brain and organ development from the embryo onwards. “Women experience constant fluctuations in hormones through every stage of life, which is an important difference from men, and has major implications for their health,” says Prof Alexandra Kautzky-Willer, head of the Gender Medicine Unit at the Medical University of Vienna.
The differences come right down to the sub-cellular level. Every cell, male or female, contains around 20,000 genes. Although these genes are virtually identical between men and women, research published by Israel’s Weizmann Institute of Science in 2017 found that around a third of them are activated (‘expressed’) differently in men and women. For example, the researchers found that the highly expressed genes in men’s skin were related to body hair growth. In all, there are an enormous number of factors at play.
“Gender health differences are the result of differences in genetic makeup, hormones, epigenetics – the effects of the environment on gene expression – and social factors,” says Kautzky-Willer.
Kautzky-Willer’s research specialises in diabetes, and she has found that men are more vulnerable to the condition later in life if their mothers endured hardship during pregnancy. She is also investigating whether separate blood tests are needed for men and women to diagnose diabetes and heart attacks. On the basis of new discoveries about differences in male and female blood chemistry, she is seeing an increasingly compelling argument that they are.
“There probably need to be different cut-offs or even different biomarkers for the same diseases,” she says. “Currently, to diagnose diabetes, you do an average blood glucose reading – HbA1c – plus a fasting glucose blood test. But we now know that women usually have lower fasting glucose and HbA1c readings than men, and you’re more likely to find women at risk if you additionally do an oral glucose tolerance test.”
Similar realisations about the need for sex-specific tests and treatments are happening in virtually every field of medicine. There’s evidence that many heart medications and anti-sickness drugs are less effective in women than men; that women are more sensitive to antihistamine drugs; that aspirin is more effective at preventing strokes in women, yet more effective at preventing heart attacks in men; that it can take women twice as long to digest medications.
The differences are clearly a matter of life and death. Though experts are reluctant to specify how many women might have lost their lives prematurely as a result of symptoms not being recognised, or inappropriate tests and treatment being administered, they do not baulk at the suggestion of hundreds of thousands.
How could this arise? How can medicine have been working for so long on the principle that women are the same as men?
The answer is that, until now, nearly all research – whether basic science on cells and animals, or trials of new drugs on humans – was carried out on males. A 2010 study from the Duke Clinical Research Institute in the US found that only a quarter of those involved in coronary artery disease trials are women.
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Dr Alyson McGregor, associate professor of emergency medicine at Brown University in the US, says that medical science over the past century has been based on only half the population. Doctors like herself have routinely ordered the same tests and medications regardless of the patient’s sex, because they were never taught to do otherwise.
The reasons for this are more complex than the undoubtedly male-dominated history of medicine, she says. In the early 1970s, there were influential legal moves in the US to protect vulnerable groups, such as women of childbearing years, from potentially harmful testing.
“It sort of eliminated women from being enrolled at all into scientific studies,” says McGregor. “And there was this general assumption at the time that women and men were similar enough, so people said, ‘let’s study men and take the results and generalise them to everyone’. That’s how a lot of our original research was established.”
Then in the 1990s came legal moves to make trials more representative by including women. “But that’s not good either,” says McGregor, “because if you’re just mixing the results they won’t be applicable to either men or women. Some studies have shown that a drug has a positive effect on men and a negative effect on women. But if we just combine the results we will never discover those differences and will have lost important clinical meaning.”
Leaders in gender medicine such as McGregor and Kautzky-Willer believe that a revolution in medical research is now required, so that data for women and men is systematically and separately gathered in every trial for every drug or treatment.
Cost is a significant barrier: one reason why drug researchers have been slow to pick up on gender medicine is that it is more expensive to have women in trials than men. It’s because of their hormonal fluctuations: for every time a man’s response to a drug needs to be checked, a woman’s will need checking several times according to where they are in the menstrual cycle. Using female mice is more expensive for the same reasons: a 2011 study from the University of California found that animals in medical research are five times more likely to be male than female.
“But there’s a moral obligation to study both men and women [regardless of cost], and there’s also the potential cost to consider of having to withdraw a drug when you find it’s harmful to women after you’ve spent a billion dollars getting it to the market,” says McGregor.
“I feel that change is inevitable now. Researchers need to design their studies to determine whether there are sex-based differences, and then their funding agencies need to ensure that possible sex differences are always taken into account. Review boards, journals, and peer review systems must do the same.” Gender medicine is already being incorporated into many medical school courses.
McGregor calls this “a new paradigm for the evolution of excellence in health care”. What she means is that gender medicine isn’t just about women. It’s about improving medicine for men as well. After all, trials that currently mix men and women are potentially making the results inaccurate for men too.
Collecting detailed information about both sexes is part of a larger process of transforming medicine, where advice is based not on the law of averages but on data for specific groups – whether they be male or female, black or white, young or old. Once the knowledge base builds and learning spreads, healthcare might look quite different.
McGregor’s junior doctors in emergency care are already taking a ‘gendered’ approach: the moment a patient walks in, they consider how their gender might affect the way a disease presents itself. Diagnostic tests are chosen according to the patient’s biological sex, and interpreted within a certain set of ranges for that sex. Treatment is prescribed according to sex-specific dosages.
The big step forward, says Kautzky-Willer, will be when pharmaceutical companies routinely take account of gender in their big trials of new drugs. “There will be costs, but it will only happen if the companies do it, because only they can afford to take on such large studies.”
She says that the companies also need to continue safety studies until there are conclusive findings for both men and women. Currently, if drugs look safe on the basis of a male-dominated sample, the ‘trend’ is believed to hold for women as well as men, and the trial is ended.
But now more and more researchers – of both genders – are involved in gender medicine, she is hopeful that a corner has been turned.
“It’s such a big field that everyone needs to be involved,” she says. “Gender medicine is not feminist, it’s about real science. We will get growing research and growing interest, and later the patient will reap the benefit.” The days of bikini medicine look numbered…
- This article was first published in BBC Science Focus in May 2019 – subscribe here