A mysterious and troubling gender disparity in the way the coronavirus attacks its victims has prompted scientists in the Bay Area and around the world to look more closely at the biology of men and women and how their bodies react to disease.
COVID-19, like many other diseases, wreaks more havoc on men than women, according to numerous studies dating to the first coronavirus outbreak in Wuhan, China, when 3 out of 4 hospitalized patients were male.
The studies have shown that men get sicker and die more often than women. In California, 56% of COVID-19 deaths are male even though about the same number of men and women get infected. In New York, male mortality has exceeded women in every age group. In Italy, 82% of the intensive care unit patients were men, according to a study conducted in February and March and published by the Journal of the American Medical Association.
The death rates for men and women vary greatly, but in every state and in all countries where records are kept, more men die from the virus than women. Infectious disease specialists estimate that, overall, about 5% more men die from COVID-19 than women.
“The data has consistently held up that males have a higher mortality rate than females,” said John Swartzberg, an infectious disease specialist and clinical professor emeritus at UC Berkeley. “It appears that men don’t handle the disease as well as females.”
Why would this be?
Faranak Fattahi, a stem cell biologist at UCSF, believes the culprit is sex hormones. Her studies at the UCSF stem cell laboratory found that androgens — male hormones, including testosterone — actually help SARS-CoV-2, the specific coronavirus that causes COVID-19, infiltrate human cells.
“The hormone itself changes the number of receptors on the cells,” Fattahi said, explaining how the jazzed-up receptors make it easier for the virus’ infamous spike proteins — or coronas — to poke inside, commandeer the cell machinery and replicate.
The fact that male pattern baldness is related to testosterone levels could mean bald men are more susceptible to COVID-19. The notion was bolstered by a preliminary study in Spain that found a disproportionate number of bald men had been hospitalized with COVID-19.
The bald thesis has been widely criticized, but Fattahi said it would fit the pattern.
“What causes baldness is high testosterone, so it’s the same underlying cause,” Fattahi said. “Male sex hormones are increasing the risk of COVID-19 severity.”
Fattahi’s team tested about 500 COVID-19 patients in the United Kingdom and the United States, many of whom had prostate disease, which is also associated with high testosterone levels. The researchers were initially looking for drugs currently in use that would reduce viral infection. While testing the drugs, the researchers noticed that the prostate patients also had particularly severe reactions to COVID-19. The common denominator between the two diseases, Fattahi said, was high testosterone levels.
“Men that had higher levels of androgen were more likely to need intensive care,” Fattahi said.“They turned out to be more susceptible to heart injury from COVID.”
The UCSF study was published as a preprint in June in bioRxiv, an open-access repository for biological studies, and is currently under peer review. Although the results are still preliminary, they are backed up by several other clinical studies linking higher androgen levels with worse COVID-19 outcomes in men.
Fattahi’s hypothesis is that the virus somehow activates dihydrotestosterone, a hormone that plays a role in puberty and the development of adult male characteristics. This active form of testosterone then initiates a process in which the enzyme TMPRSS2 is activated, making human cells more receptive to the coronavirus.
It is believed that the TMPRSS2 enzyme, commonly seen in victims of prostate cancer, latches onto the coronavirus spikes and guides them inside cells, like a key going into a lock.
Fattahi said one of the effects of this process is an increase in the level of ACE2 receptors, a protein on the surface of human cells. The coronavirus is known to target ACE2 receptors, many of which are found in the heart muscle. This may be why cardiovascular damage is common in COVID-19 patients. One study found heart damage in 12% of patients studied, and another showed it in 19% of the patients.
ACE2 receptors help regulate blood pressure and play a part in balancing hormones. The coronavirus apparently exploits these processes, which may explain why blood clots are so common in COVID-19 patients. Studies in China and France found that between 5% and 30% of hospitalized patients suffered strokes, blocked arteries or pulmonary embolisms (lung obstructions) — and a high percentage of those patients were men.
Not everybody is on board with the hypothesis. Peter Chin-Hong, an infectious disease expert and professor of medicine at UCSF, said a lot more study must be done before manliness is officially declared a liability and doctors begin prescribing therapies to wipe it away.
“I think it’s more about the male behavior rather than biology,” said Chin-Hong, who also brushed aside the notion that it is bad for one’s health to be bald. “The biology they propose is intriguing, but we need more science data.”
Until now, the prevailing thesis has been that men are generally not as healthy as women and engage more often in risky behavior — like smoking and drinking — which makes them more vulnerable to disease, especially later in life.
Men, in fact, have a shorter life expectancy and, in general, die more often than women from infectious diseases of all kinds. Studies have shown diseases like hepatitis C and tuberculosis disproportionately affect men. Heart disease, hypertension and other underlying conditions are also more common in men.
“Men in general are less healthy than women — with shorter life expectancies, worse habits,” said Julie Parsonnet, an infectious disease physician at Stanford University.
Chin-Hong said studies about infectious diseases like COVID-19 need to take into account the fact that men, at least historically, spend more time than women outdoors and are therefore in contact with mosquitoes, parasites and viruses more often.
When it comes to baldness, he said, those men are often older, and it is possible their age and relative health are greater factors than their lack of hair or testosterone level. Another potential complication that would skew the results, he said, would be if there were more bald people living in Spain than other places or, for whatever reason, Spanish men with little hair just happened to engage in more unhealthy behaviors.
“Possibly it’s the risk factor and not the biology. The male-female part could be secondary,” Chin-Hong said. “The point is, it could mean that there is something else that has a higher chance of happening. The researchers may have not controlled for everything.”
Studies have, in fact, determined that men are less likely than women to wear masks. They also generally talk louder than women, which ejects more virus droplets and may result in more infection when men hang out together.
Fattahi said none of those behaviors can account for the overwhelming difference in the severity of infections that men and women with COVID-19 typically experience.
“The majority of patients that are hospitalized are men, in some cases more than 80%,” Fattahi said. “That’s really disproportionate.”
The California Department of Public Health says 56% of the hospitalized COVID-19 patients in the state are male and 44% are female.
Fattahi’s team of researchers are testing several drugs that block testosterone. Some of the drugs are now used to treat male pattern baldness or prostate enlargement. One drug, dutasteride, has been shown to reduce the level of ACE2 receptors in the lungs, researchers say.
The researchers hope that these androgen-blocking drugs will control TMPRSS2, the enzyme that functions as a welcome mat to the coronavirus in men. Studies in Italy and the United States have shown that men with prostate cancer who took drugs to reduce their testosterone levels were as much as one-quarter as likely to contract COVID-19.
The drawback, of course, is that some of the drugs are equivalent to surgical castration, something many men might be reluctant to subject themselves to even though the treatment would be administered only until the danger passed.
Fattahi’s team is also studying the female hormone estrogen to see if it has a protective effect. And they have plans to study children to see if low hormone levels have anything to do with their low rates of coronavirus infection.
Peter Fimrite is a San Francisco Chronicle staff writer. Email: pfimrite@sfchronicle.com. Twitter: @pfimrite
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