The Upsetting Reason Why We Don't Always Know How Meds Affect Women

Illustrated by Mallory Heyer.
You probably already know that taking aspirin can be helpful for preventing heart attacks — it's the foundation of Bayer Aspirin brand's entire advertising campaign. But you probably don't know that the now-infamous 1989 landmark study that cemented the drug's effectiveness in these situations included over 20,000 men — and zero women.

Why is this? For much of medical history, men (and male animals) have been the "guinea pigs" for testing — effects, dosages, and side effects have been measured on primarily or completely male subjects. In modern medicine, men have been the model; women are often an afterthought.

Unfortunately, the trend of overlooking the effects of medications in women continues today. In 2013, 20 years after the drug first became available, the Food and Drug Administration (FDA) cut the recommended dosage of Ambien for women in half (from 10 mg to 5 mg for the immediate release version). It turns out that women — 5% of whom report using prescription sleep medications compared to just 3% of men — processed the drug more slowly than men, meaning they would feel drowsier during the day at the higher dose. This side effect comes with serious implications, including driving accidents.

Other research shows that women react to a wide variety of medications very differently from men. For instance, in one trial, male participants taking statins had significantly fewer heart attacks and strokes, but female patients did not show the same large effect. So it might, in fact, be harmful to prescribe statins — which often come with notoriously unpleasant side effects — to women with or without the risk of heart problems.

In some cases, women do better than men on SSRI antidepressants, and other research suggests that men have greater success with tricyclic drugs. Also, women who are addicted to cocaine show differences in brain activity compared to men, suggesting a mechanism by which women may become dependent on the drug more quickly. Therefore, leaving female models out of addiction studies, for example, potentially has serious implications for the drugs and standards of care that are later developed to serve addicts.

We don't know yet whether sex is going to matter across the board, but we need to know when it does.

Phyllis Greenberger
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We also know that women show different symptoms in some serious illnesses. When women have heart attacks, for example, they may or may not feel the stereotype of chest pain. Instead, they are more likely than men to experience shortness of breath, cold sweat, and lightheadedness. Although sex isn't a factor in all aspects of health, when it is, it's often serious.

"We don't know yet whether [sex] is going to matter across the board in every illness, in every condition, but we need to know when it does matter," says Phyllis Greenberger, president and CEO of the Society for Women's Health Research. She was recently a part of a congressional briefing to discuss the role of sex differences in medical research, co-sponsored by her organization and The Endocrine Society.

Greenberger's organization was also integral to helping the 1993 NIH Revitalization Act pass, which required all National Institutes of Health (NIH) funded clinical trials to include women and minority participants. Currently, this group is one of many working to get the same consideration for the animals and cells used in preclinical research — not just humans.

Thankfully, NIH is pushing to make a substantial permanent change in research. Beginning in September of last year, it began to introduce a series of policies, regulations, and incentivizing grants to encourage (and in many cases necessitate) researchers to recognize biological sex as a significant factor in their work.

"Things just continue on the way they’ve always been," says Jeffrey Mogil, PhD, at McGill University. "In this case, I think that inertia is spurred on by this expectation that is reasonable but wrong." He is referring to the basic assumption in biomedicine that female animal hormonal cycles, which fluctuate due to the estrous and menstrual cycle, will introduce another source of variability into any data collected from them.

From a scientist's perspective, the more highly controlled an experiment can be, the better the results. Also, with less variability in the animal model (like a lab rat), researchers can use fewer animals and spend less money, so many stick to exclusively using male animals simply to make things cheaper and easier.

That inertia is spurred on by this expectation that is reasonable but wrong.

Dr. Jeffrey Mogil
"That’s all fine and good," says Dr. Mogil, "except that it’s just not true." In his work, Dr. Mogil has found that variability in male and female mice data is nearly equal and, if anything, males are slightly more variable than females. A recent meta-analysis published in Neuroscience and Biobehavioral Reviews mirrors these findings, concluding that in 293 studies across all fields of biomedicine, there were no significant differences in variation between males and females.

While it's true that females have a source of variability that males don't have, Dr. Mogil says, "What everyone forgets is that...males have a source of variability that females don’t have — dominance hierarchies." This causes mice to fight in their cages when housed together and increases stress, which could make studying aggression and anxiety more difficult.

On the other hand, studying female animals and taking their hormonal changes into account isn't just introducing variability, it's introducing reality. After all, women in every stage of their cycles — and those who are pregnant, pre- and post-menopausal — need effective medication, too.

Studying female animals and taking their hormonal changes into account isn't just introducing variability, it's introducing reality.

Dr. Mogil's most recent research has focused on how mice process pain, and he's found that male and female mice actually do this through different types of immune cells. Therefore, any work looking at this mechanism only in male mice could be ignoring female pain.

"We weren’t looking for sex differences at all," he says. "[Unlike most labs,] we just use male and female mice all the time in all of our experiments... so when there are sex differences to see, we will see them." Although Dr. Mogil's current research isn't applicable to the prescription painkillers now on the market, it could be extremely valuable to the development of new ones.

Sex differences may be especially relevant to painkillers, Dr. Mogil emphasizes, because women make up 70% of chronic pain patients. So, in this field in particular, studies that look solely at male mice may end up serving a small part of the patient population.

"Sex is a biological variable that must be considered from cells to selves," writes Janine Clayton, MD, director of NIH's Office of Research on Women's Health in an email. "Every part of your body is made of cells, and each of those is either male or female — including brain cells, lung cells, and skin cells."
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We want to be sure that considering sex as a biological variable is not an afterthought.

Dr. Janine Clayton
Recently, NIH invested invested $10 million (out of a $30 billion annual operating budget) in 82 projects that are working to investigate the effects of sex on a wide range of health topics, including immune system functioning and neural circuitry. It's a small chunk, but it's a start.

Also, just last month, NIH posted a notice explaining the expectation that all grant applications (beginning in January of 2016) need to consider the effects of sex at every level — and for single-sex studies to fully justify their imbalance. If maleness has been the model up until this point, then this recent change will at least force researchers to consider and justify why.

"This policy shift intends to provoke meaningful change in the way scientists think," writes Dr. Clayton, who has been a leading force in NIH's recent policy push. "We want to be sure that considering sex as a biological variable is central, not an afterthought or a box to check."

While Dr. Mogil says the new regulations are wise, "what we really need is a cultural change — and if papers like mine start shaming people into it by showing them what they’re going to miss, then I think that’ll be a more effective way [to convince them]."

But changing minds takes a long time — and there are a lot of different minds to change here. "Going from basic research to clinical research to medical school education to the physician to the patient takes some time," says Greenberger. Still, even big changes have to start somewhere. And the attention these changes have already received is a good sign, because understanding women's health starts with actually studying them.
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