As the novel coronavirus swept through communities around the world, preying disproportionately on the poor and the vulnerable, one disadvantaged group has demonstrated a remarkable resistance. Women, whether from China, Italy or the United States, have been less likely to become acutely ill — and far more likely to survive.
Which has made doctors wonder: Could hormones produced in greater quantities by women be at work?
Now scientists on two coasts, acting quickly on their hunches in an effort to save men’s lives, are testing the hypothesis. The two clinical trials will each dose men with the sex hormones for limited durations.
Last week, doctors on New York’s Long Island started treating COVID-19 patients with estrogen in an effort to increase their immune systems, and next week physicians in Los Angeles will start treating male patients with another hormone that is predominantly found in women, progesterone, which has anti-inflammatory properties and can potentially prevent harmful overreactions of the immune system.
“There’s a striking difference between the number of men and women in the intensive care unit, and men are clearly doing worse,” said Dr. Sara Ghandehari, a pulmonologist and intensive care physician at Cedars-Sinai in Los Angeles who is the principal investigator for the progesterone study.
She said 75% of the hospital’s intensive care patients and those on ventilators are men.
And pregnant women, who are usually immunocompromised but have high levels of estrogen and progesterone, tend to have mild courses of the disease.
“So something about being a woman is protective, and something about pregnancy is protective, and that makes us think about hormones,” Ghandehari said.
Some experts who study sex differences in immunity, however, warned that hormones may fail to be the magic bullet that some are hoping for; even elderly women with COVID-19 are outliving their male peers, and there is a drastic reduction in levels of hormones for women after menopause.
The genesis of the estrogen trial at the Renaissance School of Medicine at Stony Brook University on Long Island stemmed from a similar observation, said Dr. Sharon Nachman, the trial’s principal investigator, who credited a Stony Brook surgeon, Dr. Anthony Gasparis, with the idea.
The trial enrolled its first patient this past week, and preliminary results could be available in a few months, she said.
“It’s totally out of the box, which is how good ideas often start,” said Nachman, associate dean for research at the Renaissance School, which is part of the State University of New York.
The gender gap in coronavirus survival became apparent early in the pandemic. Reports from China indicated men were dying at higher rates, but the disparity was attributed to higher smoking rates. But the outcomes were consistent in other countries, with men in Italy dying at higher rates than women and men in New York City dying at nearly double the rate of women.
Scientists who study sex differences say that both biological differences in immunity, as well as behavioral factors, are at play. Men smoke more almost everywhere, they say; men also wash their hands less. While women appear to have more robust immune systems, these experts say, the causes are complex and multifactorial, and hormones are only part of the picture.
If such sex hormones were the primary protective factor for women, then elderly women with COVID-19 would fare as poorly as elderly men, because women’s reproductive hormones plummet after menopause, said Sabra Klein, a scientist who studies sex differences in viral infections and vaccination responses at the Johns Hopkins Bloomberg School of Public Health.
But that’s not the case, she said.
“We see this bias across the life course,” Klein said. “Older men are still disproportionately affected, and that suggests to me it’s got to be something genetic, or something else, that’s not just hormonal.”
“Estrogen has immune modulatory properties — don’t get me wrong,” she continued. “You could get a beneficial effect in both men and women. But if women are better at recovery at 93 years old, I doubt it’s hormones.”
Research has shown estrogen may have an effect on a protein known as angiotensin-converting enzyme 2 (ACE2), for example. The coronavirus uses ACE2 receptors on the surfaces of cells as an entry route, and ACE2 is regulated differently in men and women, said Kathryn Sandberg, director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown University.
In studies with rats, Sandberg and her colleagues have shown that estrogen can reduce ACE2 protein expression in their kidneys, so it is possible the hormone may reduce ACE2 expression in men as well.
Nachman said, “We may not understand exactly how estrogen works, but maybe we can see how the patient does,” adding that estrogen played a complex role, both in the early immune response that could help clear a viral infection, as well as in a secondary clean up or repair response, which could evolve into a cytokine storm.
“While we see women do get infected, their responses are different,” Nachman said. “We see fewer of them having the second, disregulated immune response.”
The Stony Brook estrogen trial is recruiting 110 patients who come to the hospital’s emergency room with symptoms like fever, cough, shortness of breath or pneumonia, and who have either tested positive for COVID-19 or are presumed to have the illness, as long as they do not require intubation.
The trial is open to adult men as well as to women ages 55 and older, since they have low levels of estrogen. Half of the participants will be given an estradiol patch for one week, while the other half will serve as a control group, and researchers will follow them to see whether estrogen reduces the severity of their disease.
The Cedars-Sinai study is smaller, with only 40 subjects, all men, half of whom will be a control group. Only hospital inpatients with mild to moderate disease who have tested positive for COVID-19 can participate. (Patients with certain conditions, like a history of blood clots, are excluded for safety reasons.)
The patients will get two shots of progesterone a day for five days.
They will be monitored to see if their status is improving, how their needs for oxygen change and whether they go on to require intensive care or mechanical ventilation; their progress will be compared to patients in the control group.
The researchers in Los Angeles are pinning their hopes on progesterone rather than estrogen because research has shown that the hormone reduces pro-inflammatory immune cells and supports those that fight inflammation, Ghandehari said. The hypothesis is that progesterone will prevent or dampen a harmful overreaction of the immune system, called a cytokine storm, and will reduce the likelihood of acute respiratory distress syndrome.
Both hormones are believed to be safe, especially when used for short durations. Participants will be warned of possible side effects that may be a first for many men, like tenderness in the breast and hot flashes.