An analysis of COVID-19 patients during the initial months of the outbreak in Wuhan, China, found that men accounted for roughly 60 percent of those who were infected and became sick, according to a review published online in March 2020 in the Journal of Medical Virology. But new research published in April 2020 in Frontiers in Public Health paints a different picture: Relatively equal numbers of women and men test positive for COVID-19, but it appears to hit men harder, resulting in twice as many deaths. While experts are still unraveling the reasons, a theory has emerged: biology. RELATED: A Coronavirus Checklist: Prepare for the Possibility You May Get Very Sick
Estrogen May Help Power an Immune Response
The idea that there are sex-specific differences in how the immune system responds to disease and infection is not a new one, explains Luis Ostrosky-Zeichner, MD, a professor of medicine and infectious disease specialist at the McGovern Medical School at the University of Texas Health Science Center in Houston. At first, most experts attributed the relatively high number of COVID-19 fatalities in men to behavior and lifestyle, but it appears that the female hormone estrogen might help women fight the virus, Dr. Ostrosky-Zeichner says. Estrogen is broadly distributed in the female body, including in cells that play key roles in fighting pathogens, like bacteria and viruses. Estrogen density in immune cells helps promote the body’s first line of defense against foreign threats (called innate immunity), even when circulating levels of the hormone are declining or low — for example, throughout and after menopause. Estrogen also enhances the body’s adaptive immunity, according to a review published in October 2016 in the journal Nature Reviews: Immunology; this second line of defense mops up any remaining invaders and then builds copies of these immune cells to prevent future attacks by the same pathogens. RELATED: 10 Misconceptions About the Coronavirus
The X Chromosome May Help Fight Off the Coronavirus
“We know that a lot of the severe symptoms that occur with the coronavirus have to do with the immune system’s reaction to that virus,” says Amesh Adalja, MD, a senior scholar and pandemic expert at Johns Hopkins University Center for Health Security in Baltimore. Aside from the influence of hormones, genetic differences between men and women impact the way that their immune systems react to pathogens, according to Dr. Adalja. Researchers have observed this with other infectious diseases like influenza, for which men also tend to experience more severe illness, he says. For the novel coronavirus specifically, research has investigated the role of sex chromosomes (DNA cells that determine the genetic male or female sex). Genetic men have XY chromosomes; genetic women, XX. The presence of two X chromosomes helps women fight off the coronavirus and also prevents severe COVID-19 symptoms, suggests an editorial published online in April 2020 in the Journal of Biological Regulators and Homeostatic Agents. The interaction between a variety of genes and the X chromosome is complicated but highly orchestrated to ensure that at least one X chromosome is working with the immune system at any given time to fight pathogens when needed. Another leading hypothesis focuses on the way the coronavirus behind COVID-19 attaches to human respiratory cells. Acccording to a study published in April 2020 in MedRxiv, men have higher levels of a cell protein called ACE-2 (angiotensin-converting enzyme 2); this protein is used by the coronavirus to enter the nasal passages and, eventually, cells in the lungs and throughout the respiratory system. Researchers believe that an abundance of ACE-2 may prevent men from clearing COVID-19 from their systems, and may possibly increase their risk of dying. (This study has not yet been peer-reviewed.) Men with COVID-19 required more time than women to eliminate the virus from their lungs and respiratory system, according to a Chinese study published in April 2020 in the British Medical Journal. Men might also harbor ACE-2 in their testicles, further adding to delayed elimination and recovery time. Very little ACE-2 is found in female ovarian tissue. RELATED: Faces of Coronavirus: One Woman’s Road to Recovery
Lifestyle and Coexisting Disease Also Matter
Additional factors can affect a person’s immune response, says Adalja, adding that COVID-19 severity — and differences in men’s and women’s responses to coronavirus infection — are also believed to be influenced by coexisting medical conditions like diabetes, high blood pressure, and lung disease. Lifestyle factors such as smoking, obesity, diet, and lack of physical activity may also play a role. It’s worth noting that underlying health issues are underscored as primary drivers of more severe COVID-19 illness, according to a study published in a March Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention (CDC). RELATED: Investigators Detect Higher Incidence of Stroke in COVID-19 Patients Under Age 50
A Challenging Road Ahead
Researchers trying to better understand why men are more likely to become sicker and die from COVID-19 than women face a number of obstacles. For starters, Ostrosky-Zeichner points out that fewer women than men are included in medical research overall. And while many state and regional health systems are tracking gender differences in COVID-19 outcomes, major COVID-19 trackers such as the CDC’s COVID-19 surveillance reports do not include it. The Global Health 50-50 tracker, which is devoted to gender and health equity, notes that accurate data about gender differences and COVID-19 outcomes relies on countries reporting this information. It also says that the data that it has collected show that men have been consistently dying at a higher rate across countries where data is available. Adalja stresses that it is too early to know for certain why the coronavirus sickens men more severely than women. For now, research on the interplay of sex, genes, hormones, and lifestyle is ongoing. RELATED: How to Build Your Resilience During the COVID-19 Pandemic
