Sex Differences in Human Research
Introduction: Defining Sex Differences
Most animal species can be broken into male and female groups based on their physical differences. They often have bodies of different sizes or shapes and produce different hormones. Hormones are chemical substances produced by our bodies that are transported through blood. Males generally produce higher levels of a hormone called testosterone, and females generally produce higher levels of a hormone called estrogen. Females have a natural monthly fluctuation in hormones called a menstrual cycle. Because of these biological differences, it is unsurprising that males and females will react differently to the same experiences. Because scientists have the job of uncovering how the universe works (including human biology), it is expected that they would have studied these differences extensively in humans. But that hasn’t always been the case.
The terms “sex” and “gender” are often used interchangably, but they actually mean different things. “Sex” is used to refer to our physical characteristics at birth and is determined by a person’s chromosomes, hormones, and genitals. Gender is a little more complicated. Generally, gender reflects how a person operates in society. Gender roles and presentation are a part of this. Gender presentation is your behavior, mannerisms, interests, and appearance that are associated with a specific gender in your culture. Although both sex and gender are commonly broken into the two groups of male and female, some people may experience a gender different than their sex, and some people may not experience any one gender at all
This article will focus on sex differences and will be discussing research where biological differences are studied. Because of this, the terms “women” and “female” used within this article are referring to sex and not gender. However, in many cases, gender should also be included as a research variable in order to get the most specific results, because gender plays a large role in our daily lives and how we experience and interact with the world.
Oversights of Sex Differences in Research
Clinical research is a type of research that helps scientists determine how well medical and pharmaceutical drugs work and how much of the drug to give the patient. Every drug that will be prescribed to a patient or will be available over-the-counter is required to have extensive clinical trials conducted to determine if the drug is effective and safe enough for the general public to start taking. In the United States, the results from these trials are analyzed and approved by an organization called the Food and Drug Administration (FDA).
Ambien is the brand name for a drug commonly used to treat insomnia (generic name Zolpidem). It was approved by the FDA in 1992, however in 2013 additional tests were run that brought attention to a problem with the drug's dosage. People who took the drug at night and had side effects still experienced those side effects even into the next morning. Specifically, they had difficulty with tasks that require attention, such as driving. The reason the side effects lasted so long was because the drug was still present in their body and bloodstream. Further tests revealed that eight hours after taking Ambien, the amount of drug left in the blood was high enough to cause the bad side effects in 15% of women but only 3% of men. We know now that the reason for this difference is because women metabolize the drug (in other words, clear it from their bodies) at a slower rate than men.
Following this discovery the FDA changed the dosage recommended for women: women are now told to take half of the amount of Ambien than men are told to take. However, this change happened decades after the drug was first approved. The delay in these findings might have had consequences for the women who drove the morning after taking the higher dosage of Ambien that used to be recommended. Overall, this example shows a persistent problem in clinical research: that male and female sexes respond to medications and drugs differently. Many organizations have recently started to take steps to examine sex differences more closely.
For a very long time, women of childbearing age were excluded from all early clinical trials, although they could be included in late stage clinical trials. Childbearing age starts at puberty (around 12 years old), and goes until menopause (around 50 years old). There were two main justifications for the early clinical trial exclusion, one being that hormonal fluctuations experienced by women throughout their reproductive cycle would complicate the results. The other was that if a woman was unknowingly pregnant, that the drug being tested could potentially hurt their unborn baby. Researchers also used to believe that results from clinical trials with only men would also apply to women, which is now known to not always be the case.
A report published in 1992 compared the proportion of women in clinical trials to the proportion of women with the disease that the drug was intended to treat. They found through this analysis that the number of women represented in clinical trials was a lot less than the percentage of women in the world with the disease. Even when women were included in clinical trials, researchers did not usually check to see if women reacted differently to the drug than men. After this report the restriction of women of childbearing age was lifted, and in 1998 a final regulation was passed called the “Demographic Rule”. According to the FDA, the Demographic Rule requires drug “effectiveness data to be presented by gender, age and racial subgroups and dosage modifications be identified for specific subgroups.” However, even today most drugs are prescribed to men and women at the same dose. Since the dosage recommendations were determined based on previous studies of just male bodies, we don’t have the information on how women’s bodies will react to the same drug. Since men are usually larger than women and sometimes metabolize drugs at different rates, currently prescribed doses might not be the most effective to treat women.
The exclusion of women from research also has consequences outside of medicine. A woman wearing a seatbelt in a car during a frontal car crash has a 73% greater chance of being seriously injured than a man in the same conditions. A woman driving or sitting in the front seat of a car is 17% more likely to be killed than men. Thankfully it is unlikely for anyone to be killed in a car accident, but this gap should still be addressed. What could be causing such large sex differences? The answer may be a lot simpler than you would expect.
Automotive releases in the United States are regulated by the National Highway Traffic Safety Administration (NHTSA). They determine whether cars are safe enough to be sold. In the 1970s, the standard crash test dummy was based on the average body of an American man. These “male” dummies are 171 pounds and 5 feet and 9 inches tall. Regulators realized as early as the 1980s that female bodies perform differently in crashes, and called for a female dummy to be added to crash tests. But the NHTSA only added a female dummy in 2003. Even then, this dummy was simply a scaled down version of the male one, despite different average body shapes and builds between women and men. This “female” dummy was so scaled down, in fact, that it only represents the size of the smallest 5% of women and could be used as a test dummy for preteen children. The NHTSA also very rarely places the female dummy in the driver position during crash tests, even though one of the more dangerous places to be sitting is behind the steering wheel. Since these crash tests drive regulations for the automotive industry, the male body ends up being prioritized in car manufacturing. Fortunately modern cars are very safe, and wearing your seatbelt can protect you from a lot of injuries during a crash.
Making a change in Research
The inclusion of women in clinical research has increased significantly over the recent years due to initiatives by regulating bodies. The Demographic Rule by the FDA, mentioned earlier, did make a difference in ensuring that women were present in clinical research. The FDA now has the Office of Women’s Health which advocates for the inclusion of women in research studies both inside and outside of the FDA. They also provide training on sex differences for health professionals.
One of the largest research funding agencies in the United States, the National Institute of Health (NIH), has created a policy called Sex as a Biological Variable (SABV). This policy requires applicants for grants from the NIH to discuss how they will look at sex as one of their variables in both human and animal research. Any research that chooses not to look at sex differences has to give a good reason why they decided not to. They have developed the 4 Cs of studying sex difference. The first of these is “Consider” which is designing studies that incorporate sex as a variable. The next is to “Collect” this data. Researchers should then analyze this data based on sex differences, since grouping the sexes together can obscure results to “Characterize” this data. Once the research is completed and analyzed, the results should be “Communicated” to the public and other researchers by publishing in a scientific journal. These steps will help to make sure that sex differences are a well studied part of research.
It’s surprising to many people that research standards for medicine and manufacturing have ignored sex differences between men and women for so long. What is unsurprising are the ramifications that have taken place due to this exclusion. There are thankfully steps being taken to correct this oversight, but regulations and change can be slow. And some areas, like the NHTSA and crash test dummies, don’t seem to have much willingness to change. More awareness of and advocacy for sex differences will encourage organizations and regulators to take steps to fix the issues that have been prevalent for too long. There are many things that you can do today to spread awareness. You can share this article or one of the articles below on social media or with friends and family. Politicians often work with organizations to make regulations. You can call or write to your local congressperson to let them know that you care about making sure that sex differences are required in research.
Other Resources
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Articles to Share
Why Sex Specific Reporting is Important: https://www.ncbi.nlm.nih.gov/books/NBK84191/#:~:text=Sex%2Dspecific%20data%20could%20allow,is%20drug%2Dinduced%20electrocardiographic%20changes.
NIH Policy on Sex as a Biological Variable:
https://orwh.od.nih.gov/sex-gender/nih-policy-sex-biological-variable
Guide on Medication Safety for Women: https://www.fda.gov/consumers/womens-health-topics/medication-safety-women
Studying Sex Differences will improve health for women and men:
https://www.statnews.com/2018/06/13/studying-sex-differences-women-men/
References:
https://orwh.od.nih.gov/sex-gender
https://bsd.biomedcentral.com/articles/10.1186/s13293-020-00308-5