Biological sex and gender have a large impact on the presentation of a disease, its progression, and how it is treated, but these factors have not received adequate research or clinical attention. Positive signs of change are emerging, but there is a lot that needs to be achieved before these benefits can reach a wide range of patients.
To achieve true precision medicine, many potential factors need to be considered. An important example of this is a person’s biological sex and gender.
“Intuition tells us, but also countless scientific studies have shown that sex differences are reflected in the biology of disease, both in their etiology but also their response to treatment,” Piraye Yurttas Beim, founder and CEO of women’s health focused biotech company Celmatix, told Inside Precision Medicine.
“Studies have demonstrated that ignoring these factors in the development of medications and the treatment of disease consistently results in poorer health outcomes.”
While women and people from gender minorities are now more frequently included in clinical trials than before, there remain a lot of unknowns. For example, it is not clear how and why biological sex impacts the diagnosis and progression of many diseases. Until more research is done in this area, it will be difficult to provide informed and tailored medical care for people of all sexes and genders.
“Measuring sex as male and female in two tick boxes, that’s philosophically, methodologically, and biologically problematic. What exactly is a woman or a man?” said Petra Verdonk, a psychologist and researcher at Amsterdam University Medical Center, who has been working to help researchers implement best practices for including sex and gender in research. “Is it their hormones? Is it their genes? What exactly is it about women and men that influences health issues?”
Removing historical barriers
In the late 1950s and early ’60s, thalidomide was prescribed to thousands of women across 46 countries to treat morning sickness during pregnancy. This resulted in one of the worst drug-related adverse event scandals in living memory, with more than 10,000 children born with serious birth defects.
This scandal and others, like the use of diethylstilbestrol (DES) in pregnancy alongside thalidomide, which also caused birth defects and cancer in both mothers and children, contributed strongly to well-meaning, but ultimately misguided changes to U.S. Food and Drug Administration (FDA) guidelines.
In 1977, a new guideline was published by the FDA. It recommended that women who were able to bear children should be excluded from Phase I and early Phase II trials until possible reproductive toxicity had been checked and there was some sign of effectiveness of the candidate drug. The only women of childbearing age who were excluded from this effective ban were those with life-threatening diseases. Using contraception was not considered sufficient basis to be included in trials.
The broad application of this guideline for more than a decade led to a drastic shortage of data on women’s responses to a wide range of different medications, with clinical trials being carried out largely in men. Protests against this guideline led to the release of an National Institutes of Health (NIH) policy recommending the inclusion of women and minorities in clinical studies. Although this policy was published in the late 1980s, it did not become a legal requirement until 1993 (updated in 2017).
Despite this seemingly positive step by the U.S. government, the regulation has only impacted NIH-funded research and progress in this area has been slow. The inclusion of biologically female animals and cells in lab-based preclinical research has also lagged behind that of women in clinical trials. The NIH addressed this issue by issuing a 2016 policy stating that biological sex must be considered a variable in preclinical studies unless good justification to only study one sex can be provided.
“In order for us to get a grant funded now we have to demonstrate that we are taking into account sex as a biological variable,” explained Victoria Vieira-Potter, an associate professor in the field of nutrition and exercise physiology at the University of Missouri.
“It’s really important to consider biological sex as a variable, because it affects everything: disease state, how drugs affect us, and how food affects us … There are similarities, of course, between sexes, and some things are not sex-dependent, or divergent. But many things are.”
Building a useful knowledge base
Although knowledge about the impact of sex and gender on many diseases is lacking, some areas of medicine are more advanced than others. For example, there are significant differences in the symptoms and timing of cardiovascular disease in women and men.
Men are affected earlier in life as estrogen appears to have a protective effect in women before they attain menopause. However, numbers of events go up significantly in older, post-menopausal women and cardiovascular disease remains the biggest overall killer of women.
Nina Stachenfeld is a principal investigator at Yale University’s John B. Pierce Laboratory, whose research focuses on the impact of reproductive hormones on the cardiovascular system. “Physicians have begun to recognize and look for these different kinds of symptoms when they treat patients who are women versus men, but it took a long time for physicians to start to understand that a particular symptom that a woman’s having could actually be a cardiovascular symptom, because it’s different than that seen in men,” she explained.
“It’s a success story in the fact that I think people have become more aware than they were. But there is still a lot more that needs to be done.”
For example, the way cardiovascular disease manifests itself in transgender men and women undergoing masculinizing or feminizing hormone therapy, respectively, is less clear.
Stachenfeld and colleagues are currently studying the cardiometabolic effects of transgender transitions. Earlier studies have shown that gender-affirming hormone treatment may increase cardiovascular disease risk in both trans men and trans women, but there is currently not enough evidence to make firm conclusions.
“We found that very few people have been addressing this,” said Stachenfeld. “What we want to be able to do is find out what we think is going to happen with their cardiovascular system, or what might happen with regard to metabolism, and do everything we can to make it safe for them to continue hormone therapy.”
Another equally important area of research strongly impacted by biological sex and gender is neurology and brain disorders. Maria Teresa Ferretti is a neuroscientist and a neuroimmunologist affiliated with the Medical University in Vienna and the Center for Alzheimer Research at the Karolinska Institute in Stockholm. She co-founded a nonprofit organization called the Women’s Brain Project in 2016 that studies sex and gender differences in brain disorders.
Ferretti explained that while a lot of people are now aware of and accept differences between men and women in heart disease, brain differences seem to be harder for people to understand. “For brain or mental disorders, there is a lot of resistance … It is one thing is to say that the heart of a man is different from the heart of a woman, and very few people will argue with that. But if you say that the brain of men is different from the brain of a woman, the conversation becomes immediately political.”
Most brain diseases seem to predominantly affect females or males. For example, two thirds of Alzheimer’s disease patients and around 70% of multiple sclerosis patients are female, but Parkinson’s disease is more common in men. There are also significant sex differences in disease presentation between men and women with conditions such as Alzheimer’s, as outlined by Ferretti and colleagues in a 2018 Nature Reviews Neurology article.
“We realized that there was a gap in knowledge. When we started, almost nobody was talking about sex and gender differences in brain disorders. I started with Alzheimer’s, which is my main expertise. But soon enough, we realized that it’s a general problem,” said Ferretti.
The Alzheimer’s disease field is notorious for having many late-stage trial failures and Ferretti believes that a lack of precision medicine principles may be partly responsible for this. “By using this ‘one size fits all’ approach, we have been testing drugs on all patients and things have failed. But most likely, there may have been a subgroup of patients that could have responded.”
Since going down this avenue of research, Ferretti and colleagues have discovered sex-specific risk factors for Alzheimer’s disease. As in cardiovascular disease, hormones seem to play an important role in Alzheimer’s disease. Women seem to be diagnosed with Alzheimer’s disease or dementia later than men, perhaps due to poorly designed diagnostic tests, but decline more quickly once diagnosed.
“There is also another aspect that is largely anecdotal. There are some papers saying that a lot of women are misdiagnosed in early stages of Alzheimer’s, they’re misdiagnosed because they are sent home with a diagnosis of depression,” explained Ferretti.
“Depression is a risk factor for Alzheimer’s, so it’s not necessarily a misdiagnosis in itself. It can be that the women are depressed, but they should also be followed up and checked for potential mild cognitive impairment,” she added.
Vieira-Potter is interested in how the brain influences exercise behavior. She has discovered that there is a sex difference in the physical activity of rats and mice linked to the nucleus accumbens brain region, which is an area that drives motivated behaviors.
“We compared the brain region between females that had their ovaries and females that didn’t have their ovaries, and their running behaviors were really quite different,” she explained.
“We found stark differences in terms of genes that were changing with estrogen loss. And the genes that really came up as being strongly affected by estrogen were dopamine-related genes … the neurotransmitter that mediates reward and pleasure seeking.”
While it is hard to make direct comparisons between rodents and humans for something like exercise behavior, Vieira-Potter hopes this research will bring insights about the role of estrogen and how it is linked to reward seeking behaviors in humans.
The rocky path to implementation
Although great strides have been made in researching sex and gender differences in medicine, it is undoubtedly early days with much more to be learned. The translation of research findings into practice is also slow.
“By just assuming that men and women are exactly the same and giving them exactly the same treatments, we think we are doing a good job of considering men and women equal. We think that is gender equity, but in the end, it is not,” said Ferretti.
“You have to consider that the starting conditions can be different for men and women. It’s the difference between equality and equity. You have to make sure that you give everybody the right conditions to be able to reach the same goal.”
It has taken 30 years for a significant number of women to be included in clinical trials, but female representation is still lower than it could be. “One reason is that women are more hesitant about participating in clinical trials,” said Verdonk “In general, women have more knowledge about health and women are also more often told that they’re fragile or that their health is fragile. When there are trials or new medicines or vaccinations marketed, it’s always women’s [not men’s] fertility that’s discussed.”
Inclusion of gender minorities such as transgender or intersex people in medical research is even less common, but with the initiation of a number of new research studies, like that of Stachenfeld and colleagues, the field seems to be moving in the right direction.
Despite NIH policy changes and increasing levels of public discussion on the topic, the majority of animal experiments and cell lines are carried out on male animals or genetically male cells. “It’s important to remember that for some of the very deep mechanisms that we’re trying to study, we need those animal studies and cellular studies to answer those questions,” emphasized Stachenfeld.
Lack of funding in both academia and industry for women’s health and gender-based medicine has slowed progress in both research and implementation. For example, Bayer announced that they would be deprioritizing early R&D in women’s health in March, following the trend of companies like Merck, Pfizer, and others in the past.
Lavanya Vijayasingham is a researcher at the London School of Hygiene and Tropical Medicine. She has worked across many fields, including sex- and gender-related factors in medical research. She has also written about why acting on sex and gender in medical innovation is good for business.
“I think the time has come for industry to be the champions and explore this subject area … I was very thrilled to see GSK paying attention to sex and gender recently, alongside research and regulation processes as well,” she said.
“If there’s no buy in from industry, if there’s no value incentive perceived by them, if you’re not speaking their language, they’re not going to pick up on these things.”
Beim agrees and emphasizes that there is also significant market potential for biotech and pharma in this area. “Drugs that were specifically developed for women in the early and middle of the last century are still huge drivers of revenue for the pharma industry. In fact, these franchises are so profitable that there has simply not been an impetus to invest significantly in innovation for women’s health,” she explained.
“I believe this is short sighted as every human on earth is impacted by female biology: 100% of men were gestated inside a female body. Also, more women are surviving to advanced age than ever in human history. The unmet need, and by extension, the untapped market potential is staggering.”
- Gender Studies in Product Development: Historical Overview
- NIH Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical Research