In January, one of the first publications on those sickened by the novel coronavirus in Wuhan, China, reported that three out of every four hospitalized patients were male. Data from around the world have since confirmed that men face a greater risk of severe illness and death from COVID-19 than women and that children are largely spared. Now, scientists investigating how the virus does its deadly work have zeroed in on a possible reason: Androgens\u2014male hormones such as testosterone\u2014appear to boost the virus\u2019 ability to get inside cells.<\/p>
A constellation of emerging data supports this idea, including COVID-19 outcomes in men with prostate cancer and lab studies of how androgens regulate key genes. And preliminary observations from Spain suggest that a disproportionate number of men with male pattern baldness\u2014which is linked to a powerful androgen\u2014end up in hospitals with COVID-19. Researchers are rushing to test already approved drugs that block androgens\u2019 effects, deploying them early in infection in hopes of slowing the virus and buying time for the immune system to beat it back.<\/p>
\u201cEverybody is chasing a link between androgens \u2026 and the outcome of COVID-19,\u201d says Howard Soule, executive vice president at the Prostate Cancer Foundation, who on 13 May ran a Zoom call presenting the newest research that drew 600 scientists and physicians. A second call scheduled for today will discuss incipient clinical trials.<\/p>
Epidemiological data from around the world have confirmed the early reports of male vulnerability. In Lombardy in Italy, for example,\u00a0men comprised 82% of 1591 patients<\/a>\u00a0admitted to intensive care units (ICUs) from 20 February to 18 March, according to a\u00a0JAMA\u00a0paper. And\u00a0male mortality exceeded that of women<\/a>\u00a0in every adult age group in another\u00a0JAMA\u00a0study of 5700 New York City patients hospitalized with COVID-19.<\/p> Now, researchers are on the trail of a\u00a0mechanism for this male bias<\/a>\u2014an effort led by prostate cancer researchers, who have a deep acquaintance with androgens.<\/p> Christina Jamieson of the University of California (UC), San Diego, who has developed organoids to study prostate cancer, recalls that she was in a Zoom meeting honing ideas on how to link her research to COVID-19 when her sister, also a UC San Diego scientist, sent her a one-word text. It read: \u201cTMPRSS2.\u201d<\/p> It was 16 April, and within minutes Jamieson had found the publication that prompted the text:\u00a0a\u00a0Cell\u00a0paper<\/a>\u00a0by Markus Hoffmann of the Leibniz Institute for Primate Research and colleagues. The paper sent a lightning bolt through the prostate research community, because it showed that infection with SARS-CoV-2, the virus that causes COVID-19, relies in part on TMPRSS2, a membrane-bound enzyme. The enzyme cleaves the \u201cspike\u201d protein on the coronavirus\u2019 surface, allowing the virus to fuse with the host cell\u2019s membrane and get inside the cell.<\/p> Jamieson and other prostate cancer researchers were familiar with the enzyme, because in about half of all prostate cancers,\u00a0a TMPRSS2 mutation<\/a>\u00a0revs up an oncogene that kicks cell growth into overdrive. In the prostate, TMPRSS2 is produced when male hormones bind to the androgen receptor. \u201cDoing research, it\u2019s like you\u2019re trying to throw an anchor into the vast ocean of possibilities,\u201d Jamieson says. The discovery that TMPRSS2 helps the virus enter cells \u201cfelt like the anchor hit ground.\u201d<\/p> Researchers haven\u2019t established that androgens control TMPRSS2 in the lung\u2014ground zero for SARS-CoV-2 infection\u2014as they do in the prostate; studies in lung tissue and cells from mice and humans come to conflicting conclusions. But after the\u00a0Cell\u00a0paper was published, Andrea Alimonti, head of molecular oncology at Universit\u00e0 della Svizzera italiana, strengthened the androgen link by looking at data on more than 42,000 men with prostate cancer in Veneto in Italy. He and colleagues found that patients on androgen-deprivation therapy (ADT)\u2014drugs that slash levels of testosterone\u2014were\u00a0only one-quarter as likely<\/a>\u00a0to contract COVID-19 as men with prostate cancer not on ADT, they reported in the Annals of Oncology (see table, below). Men on ADT were also less likely to be hospitalized and to die, although numbers were small.<\/p>