During the continuing SARS-CoV-2 (COVID-19) pandemic, several studies have reported a
significant difference in the rate of severe cases between adult females and adult males (42%
vs 58%). Among children under the age of 14, the rate of severe cases was reported to be
extremely low. To explain this difference, several theories have been proposed including
cigarette smoking and lifestyle habits. However, no theory fits both the gender difference in
severe cases as well as reduced risk in pre-pubescent children. Our past research on male
androgenetic alopecia (AGA) has led us to investigate an association between androgens and
COVID-19 pathogenesis. In normal subjects, androgen expression demonstrates significant
variation between men and women as well as between adults and pre-pubescent children.
SARS-CoV-2 primarily infects type II pneumocytes in the human lung. SARS-CoV-2 enters
pneumocytes, by anchoring to the ACE2 cell surface receptor. Prior to receptor binding, viral
spike proteins undergo proteolytic priming by the transmembrane protease, serine 2 (TMPRSS2).
TMPRSS2 inhibition or knock down reduces ability of SARS-CoV-1 (a related virus to
SARS-CoV-2) to infect cells in vitro. Additionally, TMPRSS2 also facilitates entry of
influenza A and influenza B into primary human airway cells and type II pneumocytes.
The human TMPRSS2 gene has a 15 bp androgen response element and in humans, androgens are the
only known transcription promoters for the TMPRSS2 gene. In a study of androgen-stimulated
prostate cancer cells (LNCaP), TMPRSS2 mRNA expression increase was mediated by the androgen
receptor.10 Further, the ACE2 receptor, also critical for SARS-CoV-2 viral infectivity, is
affected by male sex hormones with higher activity found in males.
Androgenetic alopecia (AGA), often referred to as male pattern hair loss, is the most common
form of hair loss among men. The development of androgenetic alopecia is androgen mediated
and is dependent on genetic variants found in the androgen receptor gene located on the X
chromosome. We hypothesized that men with AGA would be more prone to severe COVID-19 disease.
We conducted a preliminary observational study of hospitalized COVID-19 patients at two
Spanish tertiary hospitals between March 23-April 6, 2020 to test this theory. In total, 41
Caucasian males admitted to the hospitals with a diagnosis of bilateral SARS-CoV-2 pneumonia
were analyzed. The mean age of patients was 58 years (range 23-79). Among them, 29 (71%) were
diagnosed with AGA (16 (39%) were classified as severe AGA (Hamilton IV or above)) and 12
(29%) did not present clinical signs of AGA. The diagnosis of AGA was performed clinically by
a dermatologist. The precise prevalence of AGA among otherwise healthy Spanish Caucasian
males is unknown; however, based on published literature, the expected prevalence of a
similar age-matched Caucasian population is approximately 31-53%.
Further, according to the European Center for Disease Control and Prevention
(https://www.ecdc.europa.eu/sites/default/files/documents/covid-19-rapid-risk-assessment-coro
navirus-disease-2019-eighth-update-8-april-2020.pdf): "Of the confirmed cases in China, 3.8%
(1 716/44 672) were healthcare workers. Of those, 14.8% were severely or critically ill and
5% of the severe cases died. Latest figures reported from Italy show that 9% of COVID-19
cases are healthcare workers, with Lombardy region reporting up to 20% of cases in healthcare
workers. In Spain, the latest COVID-19 situation overview from the Ministry of Health reports
that 26% of COVID-19 cases are in healthcare workers. In a Dutch study, healthcare workers
were tested voluntarily for COVID-19 and 6% tested positive. In a report on 30 cases in
healthcare workers in China, all cases had a history of direct contact (distance within 1
metre) with COVID-19 patients, with an average number of 12 contacts, and the average
cumulative contact time being two hours (1.5, 2.7). In the Dutch study, only 3% of the
healthcare workers reported being exposed to hospital patients with COVID-19 prior onset of
symptoms and 63% had worked while asymptomatic.
Based on the scientific rationale combined with this preliminary observation, we propose to
test an anti-androgen as a treatment for patients recently diagnosed with COVID-19. This
study is intended to explore the possible protective role of anti-androgens in SARS-CoV-2
infection, including reduction of virological duration and disease severity.