Covid-19: Why it hits men harder

Men become more ill and more likely to die from COVID-19 than women. Researchers are tracking down the causes - and drawing conclusions for future therapies

The known risk factors for a severe course of the disease Covid19 caused by the novel coronavirus include older age, obesity and previous illnesses such as diabetes and high blood pressure. Another factor apparently also plays a role - gender. Worldwide, more men have severe disease, they have to go to intensive care more often and their risk of dying is higher.

In China, this inequality is extreme. A study of over 1000 cases showed: 70 percent of the deceased were male and only 30 percent were female. The death rate in men is 2.4 times higher than in women, report researchers working with Jin-Kui Yang from the Tongren Hospital in Beijing.

Worldwide phenomenon

Data from the World Health Organization (WHO) show that the situation is similar, if not quite as blatant, in many countries around the world. If the gender ratio is mostly still balanced in the infections, the proportion of men in deaths is around 60 percent. This also applies to European countries such as Italy, England, Switzerland and the Netherlands.

Fewer infected men in Germany, but more deaths

In Germany, too, according to the Robert Koch Institute RKI, 55 percent of the deceased are men (as of May 25). At first glance, this is all the more astonishing as the proportion of those infected is now even lower than that of women. In short: more women become infected, but men become more ill and die more often.

"We see very, very many men in the intensive care unit. Between 70 and 80 percent of the patients who need intensive treatment are male," reports Catherine Gebhard. She is Professor of Cardiovascular Gender Medicine at the University Hospital Zurich. Together with colleagues from Switzerland, Germany and the USA, she has just written an overview study of clinical and epidemiological data on the subject. The possible causes are diverse and can be differentiated into biological and social.

Hormones affect the immune system

Men and viruses are often not the happiest combination - one reason for the much-cited "men's flu": the immune system of the stronger sex has a harder time with infections. "There are exceptions, for example with the dangerous influenza A, from which more women died than men. But with most viral infections, men actually have more severe courses," emphasizes Gebhard.

The immune responses have developed differently in the course of evolution. It is believed that the stronger immune response of women in the course of evolution served to protect the offspring from infections through breast milk. In fact, the female sex hormone, estrogen, boosts the immune response. In addition, many genes that are important for immune functions are on the X chromosome, of which women have two, men only one. For this reason, younger women in particular are often better equipped, for example against cold viruses. Even in earlier epidemics such as SARS or MERS, which were triggered by "relatives" of the novel coronavirus, women had milder courses and lower death rates.

Better immune response from estrogen?

"Estrogen promotes the increased formation of interferons and immunoglobulins and thus a better immune response," explains Gebhard. "It is conceivable that the female immune system becomes active at an early stage of COVID-19 due to these hormonal peculiarities, so that severe courses are less common." In addition, the "cytokine storm" often observed in severe cases would not occur in women, an overreaction of the immune system that gets out of hand and can cause massive lung damage.

Not only the immune defense, but also cell properties are hormonally influenced. The main focus here is the protein ACE2 (angiotensin-converting enzyme 2). The ACE2 receptor is a docking point for SARS-CoV-2 and enables the virus to penetrate human cells. The receptor is not only located in the airways and on the lungs, but is also found in the heart, intestines and kidneys. The concentration of ACE2 in the blood is increased in diabetics and cardiovascular patients, and it is generally higher in men than in women. One reason for this is again the sex hormones: testosterone regulates the protein up; Estrogen inhibits its spread. How all of this affects COVID-19, however, has yet to be shown in detail by studies.

Starting in June, Catherine Gebhard plans to conduct a further study with the RKI (Robert Koch Institute) and the Charité University Hospital in Berlin to find out what effect the lowering of testosterone levels has on the course of the disease. And a research group in the USA led by the infectiologist Sharon Nachman from Stony Brook University in New York wants to investigate whether administered estrogen can help men suffering from COVID-19.

Lifestyle as a risk factor

Of course, hormones alone shouldn't make the difference, because then
this protection would have to dry up in postmenopausal women. That's not the case. Even in the age group between 50 and 80, significantly more men die in this country. Only then do the curves approach each other. Many of the pre-existing conditions that make COVID-19 worse are a result of lifestyle. Obesity, diabetes or long-term smoking and a correspondingly damaged lungs are clear risk factors. And these are more common in older men in most of the world's populations than in women, who tend to be more careful about healthy eating and weight. "The COVID-19 death rate is highest among older men with previous illnesses. And there are big differences between the sexes when it comes to previous illnesses," explains Gebhard.

So women have fewer risk factors. However, that could change in the future. Although diabetes and cardiovascular diseases are even more common in men at the moment, women are following, as the doctor observes. Stress and unhealthy lifestyle habits are also increasingly part of women's life.In addition, women smoke more often today than in previous generations. It is therefore possible that the changed lifestyle will also affect the course of infections in the future.

Consequences for therapy

The gender differences also play a role in treatment. We know from previous studies that some drugs that are currently being tested against COVID-19 have different effects on men and women, such as the HIV drug Remdesivir or the malaria drug hydroxychloroquine: "Both the reactions to the drug including side effects as well as the immune response itself differ.

Hydroxychloroquine, for example, can cause cardiac arrhythmias. And women generally have a higher risk of this, "reports Gebhard. (According to recent study results, however, it is probably not effective in treating COVID-19 anyway.)

In future drug tests, such differences should therefore be carefully and carefully observed, the researcher warns. They are currently not being considered enough when it comes to the infection process.