Sex and Gender: Critical Considerations in COVID-19 Research and Response

By Emily Ortman, SWHR Communications Director

For 30 years SWHR has advocated for researchers to study sex and gender differences in health and disease in order to improve health outcomes for both women and men. The COVID-19 pandemic is providing a stark example of why sex and gender must be critical considerations in health care.

COVID-19 appears to be infecting similar numbers of women and men, but the majority of people dying from the virus are men. The initial data revealing this disparity analyzed more than 40,000 COVID-19 cases in China and showed that men accounted for nearly two-thirds of deaths.

“These data gave the first alert and laid the basis for other countries to be more alert to disaggregating their data by sex,” Dr. Ewelina Biskup, a physician and researcher in China studying the COVID-19 pandemic, said during a recent webinar titled, “Sex and Gender Differences in the COVID-19 Pandemic.”

As the virus spread globally, this disparity continued to be seen in data from country after country. Available data show that, in most countries, men have been upwards of 50% more likely to die following COVID-19 diagnosis than women. What isn’t clear is why.

“This is really the $1 million question, and the short answer is nobody knows,” Dr. Maria Teresa Ferretti said on the webinar, hosted by the Women’s Brain Project, where she is chief scientific officer.

Researchers and public health experts have offered up theories ranging from biological sex differences at the cellular level to gender differences in behavioral risk factors for COVID-19, such as smoking.

Biology at Play

Some hypotheses regarding biological sex differences center around differences in the immune systems of women and men and how the COVID-19 virus attacks cells in the human body.

Ferretti explained that COVID-19 enters cells through the ACE2 receptor, which is the same as the related coronaviruses SARS and MERS. These diseases also showed higher rates of death for men. She also said there is evidence that ACE2 activity may be influenced by the sex hormones estrogen and testosterone.

“There is a very strong indication that something biological is happening there,” Ferretti concluded.

Women also typically have stronger immune system responses than men, and both sex hormones and sex chromosome genes contribute to this difference. The X chromosome is home to a large number of immune-related genes. Women have two X chromosomes, while men have one X and one Y. Typically, one of the two X chromosomes is randomly inactivated in every cell in women, but if genes on one X chromosome are defective, women have a spare to fall back on. In addition, sometimes genes on the second X chromosome may escape inactivation.

These factors are thought to influence women’s more robust immune response generally, but they may also play a role in COVID-19 response as the gene that controls the ACE2 receptor is also located on the X chromosome.

While scientists are still working to fully understand the mechanisms behind women’s more robust immune system, in the case of COVID-19, some experts believe this immune response may be their advantage.

“My hypothesis would be, maybe females are actually mounting an initial immune response to a greater degree than our male counterparts,” Sabra Klein, a researcher at the Johns Hopkins Center for Women’s Health, Sex, and Gender Differences, told NPR earlier this month. Klein is also president of the Organization for the Study of Sex Differences, founded in 2006 by SWHR as the only scientific membership society in the U.S. dedicated to promoting research on biological sex differences.

Sex Differences in Risk

Another hypothesis is that differences in comorbidities and risk factors between women and men may be partly to blame. People at higher risk for severe COVID-19 illness include those who have lung disease, hypertension, diabetes, chronic kidney and liver diseases, as well as older people and those who are immunocompromised. Generally, men are more likely than women to develop diabetes, lung cancer, liver disease, and hypertension (specifically in younger men).

Since about half of adult men in China are smokers compared to about 2% of women, many theorized early on that this may be a contributing factor for the higher severity of COVID-19 in men. However, other countries such as Spain, where men and women smoke at similar rates, still show the male disparity in COVID-19 severity and deaths.

Meanwhile, data from Italy showed that women and men who died from COVID-19 seem to have similar numbers of comorbidities overall, but the specific comorbidities differed by sex. This counters data from Spain that showed men had a greater number of comorbidities and risk factors overall. These data also showed sex differences between women and men in the most commonly reported COVID-19 symptoms.

Of course, all of these hypotheses about COVID-19 differences in women and men have yet to be tested via controlled scientific research to determine whether they hold true.

A Call to Action

Studying sex and gender differences will help us to figure out why the virus is affecting men more severely and to understand how we can better improve our responses to future pandemics.

In order to do this research, we need reliable, consistent data about COVID-19. We need to track sex differences in deaths, symptoms, risk factors, virus exposure, and more. Unfortunately, the data currently released by the Centers for Disease Control and Prevention (CDC) does not break down U.S. COVID-19 infections and deaths by sex, although some individual states and cities are doing so. For example, as of April 22, of the 10,290 deaths in New York City, about 61% are men, and in Washington State, where the first U.S. case was identified, 55% of the deaths are men. Meanwhile, other COVID-19 hotspots like Louisiana don’t appear to be reporting data by sex.

The lack of a unified process nationwide process for reporting information on sex and gender differences in COVID-19 puts us at a distinct disadvantage in trying to understand the virus and respond adequately. A 2007 report from the World Health Organization states: “It is clear that sex and gender-related aspects of infectious diseases need to be understood better and should become an integral part of the thinking of public health officials. This would benefit both men and women as it would lead to improved outbreak control.”

The study of sex and gender differences in COVID-19 must be made a priority by the government, researchers, public health officials, and other leaders in the pandemic response efforts. Understanding the sex disparities in this disease will help us develop better vaccines, treatments and public health policies.