It’s long been known that COVID-19 is more fatal for men than women, and new research links some of that excess risk to a gene known to cause a form of hair loss in males.
A U.S. team of researchers first suspected the link when they noticed that men with a common form of hormone-sensitive hair loss, known as androgenetic alopecia, were also more prone to being hospitalized with COVID-19.
“Among hospitalized men with COVID-19, 79% presented with androgenetic alopecia compared to 31%-53% that would be expected in a similar aged match population,” said researchers led by Dr. Andy Goren, chief medical officer at Applied Biology Inc. in Irvine, Calif.
They presented their findings May 6 at the virtual spring meeting of the European Academy of Dermatology and Venereology (EADV).
The researchers noted that androgenetic alopecia is caused by the activity of the androgen receptor (AR) gene, which in some men can lead to hair loss. An enzyme called TMPRSS2, key to COVID-19 infection, is also androgen-sensitive, and might be affected by the AR gene as well, Goren’s group explained.
One key segment on the AR gene appears to affect both COVID-19 severity and the propensity of men to lose their hair due to androgenetic alopecia.
In the new study, the Irvine group conducted a genetic analysis of 65 men hospitalized with COVID-19.
They found that men with certain structural differences in the AR gene were more likely to develop severe COVID-19. Speaking in a meeting press release, Goren said the AR gene aberration “could be used as a biomarker to help identify male COVID-19 patients most at risk for ICU admissions.”
He also believes that “the identification of a biomarker connected with the androgen receptor is another piece of evidence highlighting the important role of androgens [male hormones] in COVID-19 disease severity.”
Dr. Teresa Murray Amato is chair of emergency medicine at Long Island Jewish Forest Hills in New York City and has seen many severe cases of COVID-19. She wasn’t connected to the new research, but said it “did show a significant correlation between a higher number of androgen receptors and a higher incidence of ICU admissions for patients infected with COVID-19.”
Amato added, “While the study is small and the exact association is not completely understood, it may show at least one answer to why men were more likely to be admitted to ICU and have overall higher morality with COVID-19 infections.”
According to Amato, more research is needed to determine whether “medications that block androgen receptors will be useful in treating a subset of [COVID-19] patients.”
Because the findings were presented at a medical meeting, they should be considered preliminary until published in a peer-reviewed journal.
Dr Frank Gabrin was the first American physician to die of severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection. Dr Gabrin suffered from androgenetic alopecia and was a long-term survivor of bilateral testicular cancer.1 The association between SARS-CoV-2 infectiveness and the androgen pathway has been previously described.2
Androgen-mediated SARS-CoV-2 vulnerability may help explain the disproportioned mortality rate among men.3 We present further epidemiologic evidence that androgen sensitivity might be associated with severe symptoms leading to hospitalization due to COVID-19.
Previously, we reported a possible association between male patients hospitalized with COVID-19 and androgenetic alopecia (AGA); however, the study was limited by its population size of 41 men.4 In this communication, we present additional data from patients with confirmed COVID-19 admitted due to severity criteria (mainly low peripheral oxygen saturation) to 3 tertiary hospitals in Madrid, Spain.
The patients were randomly examined by dermatologists who were assisting with the overwhelming number of admitted patients. The study took place from March 23, 2020, to April 12, 2020.
Upon admission, the dermatologists recorded the age, sex, and alopecia diagnosis. Alopecia severity was evaluated using the Hamilton–Norwood scale (HNS) for men and the Ludwig scale (LS) for women. The scores were categorized into groups: “no alopecia” for HNS = 1 or LS = 0; “moderate AGA” for HNS = 2 or LS = 1; and “severe AGA” for HNS >2 or LS >1.
A total of 175 individuals with confirmed COVID-19 were evaluated. Among the patients, 122 were men and 53 were women. Overall, 67% of the patients (95% confidence interval, 60%-74%) presented with clinically relevant AGA. The frequency of AGA in men was 79% (95% confidence interval, 70%-85%) The frequency of AGA in women was 42% (95% confidence interval, 29%-55%). The median age of female patients was 71 years (interquartile range, 22 years). The median age of male patients was 62.5 years (interquartile range, 20 years) (Fig 1, A- C).
Raw data available in Supplement 1 (available via Mendeley at https://data.mendeley.com/datasets/tphxzjkrh8/1). In both sexes, age presented great variation for those with “no alopecia,” whereas those with severe AGA presented an older age distribution and median (Fig 1, D).
Epidemiologic characteristics of 175 individuals hospitalized due to severe symptoms of COVID-19 from March 23, 2020, to April 12, 2020. A, The study population had male-to-female ratio of 2.3:1. B, Androgenetic alopecia (AGA) was present in 42% of the women and in 79% of the men. C, Notably, the violin plots demonstrate there was an older age distribution in the women compared with the men. AGA severity was categorized by specific sex scales: Hamilton–Norwood scale (HNS) for men and Ludwig scale (LS) for women into groups: “no alopecia” for HNS = 1 or LS = 0; “moderate AGA” for HNS = 2 or LS = 1; or “severe AGA” for HNS >2 or LS >1. D, Although age was widely proportional among patients with no alopecia, moderate AGA, and severe AGA, there was a slight tendency for younger age in men with moderate AGA and in women with no alopecia compared with the respective severe AGA groups. The white circle represents the median, the bar in the center represents the interquartile range, and the thin lines represent the 95% confidence interval. The wider sections of the violin plot represent a higher probability that members of the population will take on the given value and the thinner sections represent a lower probability.
The prevalence of age-matched men in a similar white population was estimated to be 31% to 53%,4 whereas in women, the highest AGA prevalence reported (with dermatologist evaluation) was 38% in patients aged >69 years.5 Age group comparison with other references available in Supplement 2 (available via Mendely at https://data.mendeley.com/datasets/jk63cthxbr/2). In our data, 57% of females >69 years old were diagnosed with AGA. These results indicate that a substantial proportion of individuals hospitalized for severe COVID-19 in your centers have AGA.
The hypothesis of androgen-mediated COVID-19 severity requires validation in larger studies. Antiandrogen treatments that could be theoretically studied in the treatment and prophylaxis of severe COVID-19 are indicated in Fig 2 . Therapeutic randomized controlled clinical trials with bicalutamide (NCT04374279), degarelix (NCT04397718), and spironolactone (NCT04345887) are currently underway.
Possible targets of the androgen pathway for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prophylaxis and adjuvant therapy. Antiandrogen therapies include gonadotropin-releasing hormone (GnRH) analogs (degarelix, goserelin, leuprolide, leuprorelin, nafarelin), which stop luteinizing hormone (LH) secretion and induce chemical castration. Testosterone is regarded as the main androgen hormone, and its production is inhibited by ketoconazole, an inhibitor of steroidogenesis. Dutasteride and finasteride, 5-α-reductase inhibitors, target synthesis of dihydrotestosterone, the most potent intrinsic androgen hormone. Androgen receptor inhibitors may be steroidal (abiraterone, cyproterone, nomegestrol, or spironolactone), or nonsteroidal (apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, or nilutamide). Transmembrane protease, serine 2 (TMPRSS2) blockers include bromhexine, camostat, and nafamostat. ACE, Angiotensin converting enzyme.
The sample size and lack of a control group and outcomes are limitations of this study. Because dermatologists actively graded AGA, observer bias was possible. The precise AGA rate in an age-matched, not-admitted population with COVID-19 is still unknown to draw further conclusions. Future studies could evaluate whether lung involvement correlates with the severity of AGA or whether the proportion of AGA is higher in intensive care/fatal COVID-19. AGA severity reflects androgen activity over age, which are 2 vulnerability characteristics for COVID-19. AGA is a primary individual characteristic, different from telogen effluvium, which occurs after months of the stress of illness.
Finally, because Dr Gabrin was the first physician to die from COVID-19 in the United States, we propose the use of the eponym the “Gabrin sign” to visually identify patients at higher risk for severe symptoms after COVID-19 infection.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242206/
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