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Theory
Androgen-driven COVID-19 pandemic theory
Carlos Gustavo Wambier,1* Andy Goren,2 Angelina Ossimetha,3 Gerard Nau,1
Abrar A. Qureshi,1
1Warren Alpert Medical School of Brown University, Providence, RI, United States.
2Applied Biology, Inc. Irvine, CA, United States.
3Brown University, Providence, RI, United States.
Corresponding author:
Prof. Carlos Gustavo Wambier
Department of Dermatology, Rhode Island Hospital - 593 Eddy Street, APC, 10th Floor
Providence, RI, USA. 02903
Email: carlos_wambier@brown.edu
Electronic copy available at: https://ssrn.com/abstract=3571863
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Graphical Abstract
Summary
This theory article introduces the plausible essential role of androgen receptor for
SARS-CoV-2 infection. The androgen-driven COVID19 pandemic theory, based on the
androgen receptor activation for the transcription of transmembrane protease, serine 2
(TMPRSS2), explores possible implications in risk stratification and transmissibility. A
theorical COVID-19 viral load spectrum of disease is proposed, ranging from a
resistance pole (pauciviral) to a vulnerability pole (multiviral). This theory could
explain why males seem to be more vulnerable, and why children are more resistant to
infections before adrenarche and puberty. Androgen receptor gene polymorphisms have
been linked with other known risk factors such as hypertension and possibly ethnicity.
Future studies are required to validate this theory and to evaluate the therapeutic and
prophylactic potential of medications that temporarily target androgen activity, such as
androgen receptor inhibitors, steroidogenesis inhibitors, 5-alpha reductase inhibitors,
and chemical castration with GnRH analogues.
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Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lethality is thought to
primarily afflict vulnerable individuals with pre-existing conditions. The individual risk
has been originally attributed to low adaptive reserve to lung inflammation or hypoxia,
such as physical and metabolic senescence, multiple co-morbidities, cardiovascular
disease, and prior history of pulmonary disease. All of these are all attributed to the
COVID-19 disease severity and mortality (Bialek et al., 2020). However, this disease
mortality risk model, which commonly succeeds to evaluate risks for cardiovascular
disease, fails to explain gender disparities in COVID-19 mortality as well as the small but
not insignificant amount of otherwise healthy young adults that have died following
SARS-CoV-2 infection. Most notably, Dr Li Wenliang, a previously healthy 34-year-old
Chinese doctor that first alerted the world to the SARS-CoV-2 epidemic (Petersen et al.,
2020).
A recent study reported that males are at an increased risk for the development of severe
symptoms following SARS-CoV-2. The study utilized a multivariate analysis of 487
cases from Wuhan, China (Shi et al., 2020). The analysis of variables independently
associated with severe COVID-19 disease at admission showed that male gender was the
most important independent risk factor with odds-ratio (OR) of 3.68 [95% confidence
interval (CI) 1.75–7.75], compared to the diagnosis of hypertension, OR 2.71 [95% CI
1.32–5.59], and age over 50 years, OR 1.06 [95% CI 1.03–1.08]. Several other studies
have reported a significant difference in the incidence and percentage of severe cases
between females and males. Among 1099 cases reported in one study 58% were male,
and among the 67 patients with severe disease which needed intensive care, non-invasive
ventilator or that died 67% were male (Guan et al., 2020). In addition, epidemiological
observations note milder symptoms and infection rates in children. In a review of 72,314
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cases by the Chinese Center for Disease Control and prevention, children less than 10
years of age accounted for less than 1% of the total cases, with no fatal reports (Wu and
McGoogan, 2020). In the series of 1099 laboratory confirmed cases, only 9 (less than 1%)
were below 14 years of age, among which only 1 had severe disease that did not require
intensive care (Guan et al., 2020). In one study, among 1391 children from 0-15 years-
old actively tested for suspected SARS-CoV-2, only 171 (12%) had a positive test (60.8%
were male), among the 171 positive tests, 15% were asymptomatic and 20% were
oligosymptomatic (Lu et al., 2020). Another epidemiologic study in 36 children younger
than 16 years reported higher prevalence of COVID-19 in males (64%) (Qiu et al., 2020).
Another case report of a male newborn was documented with uneventful rhinitis and
cough. The newborn was in close contact with his father suffering from upper airway
infection and conjunctivitis (Canarutto et al., 2020). A possible explanation for the higher
mortality rate and disease severity among male patients as well as the extremely low
mortality rate among pre-pubescent children may be due to the action of androgens on
lung tissue. We present the various mechanisms thought to drive SARS-CoV-2 viral
infection.
TMPRSS2 and SARS-CoV-2
The first biological step required for viral infectivity of the SARS-CoV-2 virus is priming
of the spike proteins by transmembrane protease, serine 2 (TMPRSS2). TMPRSS2 is
expressed on the surface of type II pneumocytes in human lung tissue. Although other
proteases found to activate the spike proteins in vitro, only TMPRSS2 activity is regarded
as essential for viral entry and replication in infected hosts (Hoffmann et al., 2020).
TMPRSS2 may also cleave angiotensin converting enzyme 2 (ACE2) for augmented viral
entry, as has been shown for SARS-CoV-1 (Heurich et al., 2014).
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Androgens and TMPRSS2 gene expression
The transmembrane protease, serine 2 (TMPRSS2) gene is located to the human
chromosome 21q22.3, it encodes a 492-aminoacid polypeptide with five distinct domains:
a serine protease domain, a scavenger receptor domain, low-density lipoprotein domain,
a transmembrane domain, and a cytoplasmic domain (Paoloni-Giacobino et al., 1997).
Androgen receptor activity is required for the transcription of TMPRSS2 gene as no other
regulatory element of the TMPRSS2 promoter has been described in humans to date
(Lucas et al., 2014; National Institutes of Health, 2020). The human TMPRSS2 promoter
has a 15-bp androgen response element at position 148 relative to the putative
transcription start site. In addition, TMPRSS2 mRNA expression was found to be
androgen regulated in prostate cells (Lin et al., 1999), and the androgen receptor is
responsible for the upregulation of TMPRSS2 mRNA (Afar et al., 2001). Androgen
treatment induced increased TMPRSS2 zymogen activation in cell culture and in a mouse
xenograft model, suggesting androgens regulate TMPRSS2 on transcription and post-
translation levels in intrinsically dependent manner (Afar et al., 2001). The TMPRSS2
gene is expressed mainly in the adult prostate, but also expressed in multiple other tissues,
particularly in human adult colon, small intestine, pancreas, kidney, lung and liver
(Jacquinet et al., 2001) and in fetal lung and kidney (Paoloni-Giacobino et al., 1997,
2001). This transmembrane protease, has also been called human epitheliasin (Jacquinet
et al., 2001).
Besides the TMPRSS2 expression in the target organs for COVID-19, lungs, liver, and
kidneys (Gu et al., 2020), ACE2 receptor is also expressed in these organs and in the
prostate (Xu et al., 2020). ACE2 is implicated in SARS-CoV-2 viral anchoring to the cell
surface, is also affected by androgens, with higher activity found in males (Dalpiaz et al.,
2015).
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Androgen expression and COVID-19
Male susceptibility to the development of severe COVID-19 symptoms may be further
enhanced by X-linked inheritance, since both the androgen receptor gene and the ACE2
genes are located on the chromosome, Fig.1.
Figure 1. Theorical rate-limiting role of androgens in COVID-19 infection. Red arrows
show the pathway for SARS-CoV-2 virus infection mediated by androgen activity.
Dihydrotestosterone (DHT) is the most potent intrinsic androgen hormone, and requires
intracellular 5-alpha-reductase activity. Testosterone is regarded as the main androgen
hormone, which activates the androgen receptor with less affinity than DHT in cells that
do not express 5-alpha-reductase.
Androgen sensitivity may be an important factor for disease severity, which would also
explain severe cases in female patients who present with metabolic syndrome, or are using
birth control methods with progestogen hormones that bind to androgen receptor. Several
studies have demonstrated that androgen sensitivity is associated with the CAG repeat in
the first exon of the androgen receptor gene (AR). Shorter CAG repeat length pre-dispose
men to develop androgenetic alopecia, acne and oily skin; therefore, we believe that CAG
repeat in the AR gene may be associated with increased COVID-19 disease severity and
mortality. An interesting observation supporting our theory is the disproportionate
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mortality rate observed in African American COVID-19 patients.(Thebault et al., 2020)
African Americans as an ethnic group, tend to carry a shorter version of the CAG repeat
in the androgen receptor gene,(Bennett et al., 2002) Fig.2.
Figure 2. Following the androgen-driven COVID-19 theory, subjects with increased
androgen receptor activity, either through androgen receptor gene polymorphism or
through hyperactivation by androgen hormones are predisposed to increased viral load,
which would reflect on pronounced symptoms and transmissibility from cell lining of the
airways and digestive tract. A spectrum of androgenic activity would imply in polar
pauciviral COVID-19 (ex: children<7), with null airway/fecal transmission potential,
women with normal androgen activity would have low transmission potential (borderline
pauciviral COVID-19), male teenagers and adults would have high transmission potential
(borderline multiviral COVID-19), and infected individuals with abnormally high
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androgen receptor activity (genetic or acquired) would represent the multiviral COVID-
19 pole of the spectrum, with extremely high transmission.
Figure 3. Gross testosterone levels per gender, from birth to 85 years of age. Note
peak in newborn males, and increase in testosterone levels in both genders after
puberty. There is a subtle decrease in testosterone levels with aging. Adapted from:
Ober C et al. Sex-specific genetic architecture of human disease. Nat Rev Genet.
2008;9(12):911-922.
Hyperandrogenic conditions in females
Many are the conditions that could increase androgen activity in females, increasing
vulnerability to COVID-19. Generally, in the same age group, females have much lower
levels of testosterone than males.(Ober et al., 2008) Monthly fluctuations in androgen
hormones occur during the menstrual cycle, however some conditions are known to
increase androgen hormone levels in female patients. Congenital adrenal hyperplasia
(CAH) is a class of autosomal recessive disorders characterized by a specific hormone
deficiency referred to as 21-hydroxylase deficiency. 21-hydroxylase deficiency results in
excess adrenal precursors which are excessively metabolized into androgens i.e.,
testosterone and dihydrotestosterone (DHT), (White and Speiser, 2000) Fig.4.
Studies suggest that females with 21-hydroxylase deficiency have a higher risk for a host
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of medical conditions. Some females with 21-hydroxylase deficiency fit diagnosis criteria
for polycystic ovary syndrome (PCOS) (New, 2006). A common characteristic of PCOS
is hyperandrogenism.(Bani Mohammad and Majdi Seghinsara, 2017) PCOS is a very
common disease among females of reproductive age. Depending on the criteria used,
PCOS prevalence ranges from 4 to 21% (Lizneva et al., 2016). Furthermore, metabolism
has a direct relationship with hyperandrogenism in females, genetically higher
testosterone levels in females was associated with increased risk of type 2 diabetes (odds
ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22–1.53)) and polycystic ovary
syndrome (OR = 1.51 (95% CI: 1.33–1.72)), while higher testosterone levels reduce type
2 diabetes risk in men (OR = 0.86 (95% CI: 0.76–0.98))(Ruth et al., 2020).
Coincidently, PCOS is associated with a shorter version of the CAG repeat in the
androgen receptor gene (Schüring et al., 2012).
Regarding female factors, external hormones might play a significant role in COVID-19
pandemic statistics. Progestins hormonal birth control is commonly used. Progestin affect
on the androgen receptor is not well understood. Progestins acts as both agonist and
antagonist depending on the particular progestin. Progestins may have potent agonist
action in androgen receptors, similar to DHT, such as levonorgestrel, gestodene,
medroxyprogesterone and norethisterone (Africander et al., 2014; Louw-du Toit et al.,
2017). Others might have strong antagonist effects, such as cyproterone, which was found
to be a stronger antagonist than nomegestrol (Duc et al., 1995). In a recent comparative
study (Louw-du Toit et al., 2017) nomegestrol was found to be an antagonist with superior
effects than hydroxyflutamide. Hydroxyflutamide is the active metabolite of a known
non-steroidal androgen receptor antagonist, flutamide. Hydroxyflutamide showed to have
comparable AR antagonism to progesterone and drospirenone, and a weaker antagonism
was found with nestorone.
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Figure 4. Steroidogenesis. 21-hydroxylase deficiency causes increased production of
androgen hormones. Male patients who take external androgens may accumulate
dihydrotestosterone, particularly with use of aromatase inhibitors. (source: Wikimedia
commons).
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Considerations
Although authors suggest the main role of androgens by current known mechanisms of
the disease, other unknown pathways for SARS-CoV-2 infection might play a role,
including antibody-mediated phagocytosis (which could cause infection in some cells)
and other receptors that do not require priming by enzyme proteases. Table I lists some
strategies to verify if the androgen receptor activity is truly the key to the SARS-CoV-2
infection.
Conclusions
The role of androgens on COVID-19 disease severity and mortality could explain the
gender bias in mortality rates. In addition, our androgen driven theory explains the low
rate of mortality among pre-pubescent children and the higher rate of mortality observed
in the African American population. A rapid epidemiological study of disease severity
among men prescribed anti-androgens for benign prostatic hyperplasia vs aged match
controls may further demonstrate the validity of our theory. In addition, a study of the
CAG repeat length in deceased COVID-19 patients compared to patients that have been
dismissed from hospitalization may enable the development of a diagnostic to accurately
identify vulnerable individuals. Finally, if our theory is proven correct, aggressive anti-
androgen therapy could be used in high risk infected patients. In addition, if a vaccine is
not found, androgen suppression as a prophylactic treatment could reduce host
vulnerability, particularly for subjects with increased infection risk, such as healthcare
workers, police officers, and the military.
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Table I. Suggested methods to evaluate possible independence of the androgen receptor
to TMPRSS2 gene expression:
in vitro
-AR Knock-out cell cultures expressing TMPRSS2 gene
i.e.: assay of SARS-CoV-2 in Vero cells cultures.
in vivo
- Knock-out AR COVID-19 animal infection experiment.
epidemiological studies
- Total Androgen Insensitivity syndrome: single case
report.
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