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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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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
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Graphical Abstract
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.
Electronic copy available at:
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.,
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
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.,
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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.
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
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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
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
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... Its additional anti-androgen effects, which have always been considered to be drawbacks of spironolactone, are also important in coronavirus disease. This is particularly important in COVID-19, since activation of both the ACE2 receptor and the transmembrane serine protease is direct ly related to male sex hormones and hyperactivation of androgen receptors [14]. This explains the faster develop ment and progression of the disease in male patients, especially those with severe hypergonadism [15,16]. ...
... The results questioned the correctness of choosing a single time endpoint, i.e., 10 days of treatment, since significant differences between the groups were noted earlier and could disappear by day 10. This is also known from other trials [21,14]. EDITORIAL ARTICLES § Thus, we performed additional tests, including the virus detection using PCR. ...
... Retrospectively, it is obvious that an additional intermediate test on days 4-5 could haved revealed earlier and more significant benefits of EDITORIAL ARTICLES § bromhexine and spironolactone therapy compared to the standard management of patients with COVID-19. Other researchers have reported similar observations [21,14]. We observed no side effects in the bromhexine / spironolactone group under our protocol compared to 4.33 % in the control group. ...
Introduction The aim of this study was to assess the efficacy and safety of a combination of bromhexine at a dose of 8 mg 4 times a day and spironolactone 50 mg per day in patients with mild and moderate COVID 19. Material and methods It was an open, prospective comparative non-randomized study. 103 patients were included (33 in the bromhexine and spironolactone group and 70 in the control group). All patients had a confirmed 2019 novel coronavirus infection (COVID 19) based on a positive polymerase chain reaction (PCR) for SARS-CoV-2 virus RNA and/or a typical pattern of viral pneumonia on multispiral computed tomography. The severity of lung damage was limited to stage I-II, the level of CRP should not exceed 60 mg / dL and SO2 in the air within 92-98%. The duration of treatment is 10 days. Results The decrease in scores on the SHOKS-COVID scale, which, in addition to assessing the clinical status, the dynamics of CRP (a marker of inflammation), D-dimer (a marker of thrombus formation), and the degree of lung damage on CT (primary endpoint) was statistically significant in both groups and differences between them was not identified. Analysis for the group as a whole revealed a statistically significant reduction in hospitalization time from 10.4 to 9.0 days (by 1.5 days, p=0.033) and fever time from 6.5 to 3.9 days (by 2.5 days, p<0.001). Given the incomplete balance of the groups, the main analysis included 66 patients who were match with using propensity score matching. In matched patients, temperature normalization in the bromhexine/spironolactone group occurred 2 days faster than in the control group (p=0.008). Virus elimination by the 10th day was recorded in all patients in the bromhexine/spironolactone group; the control group viremia continued in 23.3% (p=0.077). The number of patients who had a positive PCR to the SARS-CoV-2 virus on the 10th day of hospitalization or longer (≥10 days) hospitalization in the control group was 20/21 (95.2%), and in the group with bromhexine /spironolactone -14/24 (58.3%), p=0.012. The odds ratio of having a positive PCR or more than ten days of hospitalization was 0.07 (95% CI: 0.008 - 0.61, p=0.0161) with bromhexine and spironolactone versus controls. No side effects were reported in the study group. Conclusion The combination of bromhexine with spironolactone appeared effective in treating a new coronavirus infection by achieving a faster normalization of the clinical condition, lowering the temperature one and a half times faster, and reducing explanatory combine endpoint the viral load or long duration of hospitalization (≥ 10 days).
... However, strong immune responses in females may also lead to immunopathology, resulting in fatal outcomes [4]. Another possibility is that testosterone facilitates cell entry by SARS-CoV2 and is one of the driving factors of the epidemic ("androgen-driven COVID-19 pandemic theory") [12,13]. Infectivity of COVID-19 depends on priming of the spike proteins by transmembrane protease, serine 2 (TMPRSS2) [14,15], and TMPRSS2 may cleave angiotensin converting enzyme 2 (ACE2) for augmented viral entry [16]. ...
... Infectivity of COVID-19 depends on priming of the spike proteins by transmembrane protease, serine 2 (TMPRSS2) [14,15], and TMPRSS2 may cleave angiotensin converting enzyme 2 (ACE2) for augmented viral entry [16]. Importantly, androgen receptor activity is a requirement for the transcription of the TMPRSS2 gene, suggesting that testosterone facilitates SARS-CoV2 cell entry [12,13]. ...
... The androgen-driven COVID-19 pandemic theory concerns circulating levels of testosterone and has some support from the relationship between age-related COVID-19 mortality rates. For example, it may explain why children are more resistant to infections before adrenarche and puberty [12,13]. Thus, high mortality from SARS-CoV2 in men should be related to hypergonadism and to low (masculinized) 2D:4D. ...
Background The reported national case fatality rates (CFRs) for coronavirus disease 2019 (COVID-19) shows a sex bias with males > females. The relative lengths of the index (2D) and ring (4D) fingers (digit ratio; 2D:4D) is a sexually dimorphic (males < females) proxy of fetal sex steroids (low 2D:4D indicates high prenatal testosterone/low prenatal estrogen). Aim To examine sex-specific relationships of 2D:4D per nation with national values of COVID-19 CFRs. Study design: COVID-19 CFRs and the percent of male deaths were related to mean national (self-reported) 2D:4D by sex and hand from a large online survey (the BBC Internet Study). Subjects 103,482 men and 83,366 women. Outcome measures Relationships of mean national 2D:4D with CFRs from 41 countries and with national male death rates from 16 countries. Results Male right and left hand 2D:4D showed positive relationships with CFR. These relationships remained significant after removing the influence of female 2D:4D. A positive association of male right and left 2D:4D was detected with the percentage of male deaths. Conclusions At the national level, high mean 2D:4D (indicating low prenatal testosterone/high prenatal estrogen) is associated with high CFRs and percent male mortality. At the individual level, high 2D:4D may be a risk factor for severity of COVID-19 in males. We speculate that male 2D:4D is a negative correlate for expression of the SARS-CoV2 receptor (ACE2).
... This led to the elimination of hypogonadism in 28 patients -40%. Patients with persistent hypogonadism were statistically significantly older than men with normalized testosterone, there were no statistically significant differences in the initial levels of total testosterone, SHBG and free testosterone, and there were also no differences in the prevalence of severe 97[2,86;7,46] vs 4,26[2,93;5,96] nmol/ ...
... Так, было отмечено, что те пациенты, которые получают андрогендепривационную терапию, реже заболевают и легче переносят SARS-CoV-2, и этот эффект исследователи объясняют воздействием на белок TMPRSS2, синтез которого является андрогензависимым [5]. В других исследованиях было установлено, что как экспрессия TMPRSS2, так и более тяжелое течение коронавирусной инфекции отмечаются у мужчин с гиперандрогениейандрогенной алопецией, акне, выраженным лицевым оволосением и повышенной жирностью кожи [6][7][8]. Однако в исследовании G. Rastrelli и соавт. (2020) было показано, что низкие уровни тестостерона связаны с худшим прогнозом коронавирусной инфекции у мужчин [9]. ...
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BACKGROUND . COVID-19 is a disease that has a negative systemic effect on the human body, including the male gonads. Therefore, the androgenic status in men with COVID-19 needs to be studied. AIM . To evaluate the levels of total testosterone, sex hormone binding globulin (SHBG) and free testosterone in men in the acute phase of COVID-19 and during convalescence. MATERIALS AND METHODS . A continuous dynamic prospective study of 70 men with moderate to severe COVID-19 at the age of 50[44; 64] years. During the study, the levels of total testosterone, SHBG were determined with further calculation of the level of free testosterone by Vermeullen. The data were collected twice — at the patient’s hospitalization and at his discharge. The differences between the groups were considered statistically significant at p <0.05. RESULTS . At the time of hospitalization for COVID-19, hypogonadism syndrome was observed in 61 people — 87%. Patients with hypogonadism did not statistically significant differ in age and severity of COVID-19 disease compared to men without hypogonadism. Inpatient treatment lasting 12[10;14] days resulted in a statistically significant increase in the levels of total testosterone from 4,7[2,96;8,48] to 12,85[8,62;19,2] nmol/l, p<0,001; SHBG from 27,87[20,78;36,57] to 33,76[26,27;52,60] nmol/l, p<0,001 and free testosterone from 107[65;174] to 235[162;337] pmol/l, p<0,001. This led to the elimination of hypogonadism in 28 patients — 40%. Patients with persistent hypogonadism were statistically significantly older than men with normalized testosterone, there were no statistically significant differences in the initial levels of total testosterone, SHBG and free testosterone, and there were also no differences in the prevalence of severe COVID-19 (3,97[2,86;7,46] vs 4,26[2,93;5,96] nmol/l, p=0,100; 28,76[20,78;48,59] vs 24,63[18,85;31,70] nmol/l, р=0,994; 100[58;118] vs 96[64;143] pmol/l, p=0,522; 24 против 18%, p=0,754, respectively). CONCLUSION . COVID-19 has a pronounced negative effect on the production of testosterone in men, leading to the development of laboratoric hypogonadism, which is potentially reversible. The reversibility of laboratoric hypogonadism is typical for younger patients.
... Кроме стимулирующего влияния на экспрессию АПФ-2, мужские половые гормоны ответственны за синтез трансмембранной сериновой протеазы 2 типа, обеспечивающей вход вируса SARS-CoV-2 в клетки [29]. Причем максимально быстрое прогрессирование COVID-19 отмечается у мужчин с высоким уровнем тестостерона, который как раз и стимулирует активацию трансмембранной сериновой протеазы 2 типа [30,31]. В Испании нашли связь между облысением у мужчин, уровнем тестостерона и тяжестью новой коронавирусной инфекции [32]. ...
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The article attempts to analyze the change in philosophy in approaches to the treatment of COVID-19 that have occurred in recent months, based on published research and their own experience in the treatment of a new coronavirus infection at the medical research and education center of Moscow state University. Emphasis is placed on the rationale for the phased use of different types of therapy. The reasons for using spironolactone in patients with COVID-19 as a drug for etiotropic and pathogenetic therapy are discussed in detail. The authors conclude that the use of antiviral drugs in combination with drugs that prevent the entry of the SARS-CoV-2 virus into cells from the first days of the disease should be supplemented with pre-emptive anti-inflammatory therapy that interrupts the progression of the disease. The parallel use of anticoagulants that reduce the risk of thrombotic and thromboembolic complications.
... Recently, impaired testosterone production from testes in males has been reported 36 , coherently with the corresponding tissues showing the highest ACE2 expression. In fact, androgens and androgen receptor (AR) have been known to affect ACE2 and TMPRSS2 expressions 37,38 . This implies that patients with prostate cancer that are treated with anti-AR therapy could be less susceptible to viral infection. ...
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. One open question is whether genetics could influence the severity of symptoms. Considering the limited data on cancer patients, we analyzed public data repositories limited to investigate angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) expressions and genetic variants to identify the basis of individual susceptibility to SARS-CoV-2. Gene expression and variant data were retrieved from Tissue Cancer Genome Atlas, Genotype-Tissue Expression, and gnomAD. Differences in gene expression were tested with Mann-Whitney U-test. Allele frequencies of germline variants were explored in different ethnicities, with a special focus on ACE2 variants located in the binding site to SARS-CoV-2 spike protein. The analysis of ACE2 and TMPRSS2 expressions in healthy tissues showed a higher expression in the age class 20 to 59 years (false discovery rate [FDR] < 0.0001) regardless of gender. ACE2 and TMPRSS2 were more expressed in tumors from males than females (both FDR < 0.0001) and, opposite to the regulation in tissues from healthy individuals, more expressed in elderly patients (FDR = 0.005; FDR < 0.0001, respectively). ACE2 and TMPRSS2 expressions were higher in cancers of elderly patients compared with healthy individuals (FDR < 0.0001). Variants were present at low frequency (range 0% to 3%) and among those with the highest frequency, the variant S19P belongs to the SARS-CoV-2 spike protein binding site and it was exclusively present in Africans with a frequency of 0.2%. The mechanisms of ACE2 and TMPRSS2 regulation could be targeted for preventive and therapeutic purposes in the whole population and especially in cancer patients. Further studies are needed to show a direct correlation of ACE2 and TMPRSS2 expressions in cancer patients and the incidence of COVID-19.
... Male susceptibility to the development of severe COVID-19 symptoms may b e f u r t h e r e n h a n c e d b y X -l i n k e d inheritance, since both the androgen receptor gene and the ACE2 genes are located on chromosome X. 8 To study this hypothesis two clinical trials have been initiated, one in New York which has commenced treating COVID-19 patients with estrogen, and the other in Los Angeles which will treat male patients with progesterone, which has anti-inflammatory properties, and can potentially prevent harmful overreactions of the immune system. 9 P r o t e c t i o n i n f e m a l e s h a s b e e n postulated to be either due to XX linkage or estrogens with its role in negative regulation of the serene p r o t e a s e s i n c l u d i n g T M P R S S 2 . 1 0 A n o t h e r p o s t u l a t e a t t r i b u t e s t h e increased male vulnerability to high ACE2 receptor concentrations in the testis. ...
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Whilst COVID-19 infection generally run a mild course in up to 80% of those affected, a number of pre-existing co-morbidities determine the severity of infection and the outcome in an individual patient. The most important of these co-morbidities that have consistently emerged in studies from across the globe, are the patients age and sex. Other important co-morbidities that adversely affect outcomes include pre-existing diabetes, obesity, hypertension, chronic lung disease and malignancy. This comprehensive review discusses the impact of these co-morbidities and the role of laboratory predictors of poor patient outcomes age was directly linked to death, with exponential rise over the age of 50 years. On binary division of age groups, death rates were 0.32% in the < 60 years age group and 6.38% in > 60 years age group. Highest death rate (14.8%) was seen in the age group >80 years. 4
... Wambier et al in their exploration of the Covid pathogenesis explain in their hypothesis why males seem to be more vulnerable reporting higher mortality rates, and attribute it to androgen receptor gene polymorphisms. 20 Based on this, it was suggested that agents halting androgen activity, such as androgen receptor inhibitors, steroidogenesis inhibitors, 5-alpha reductase inhibitors may play a role in therapeutics. ...
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SARS‐CoV‐2 is a novel single stranded RNA virus that has gripped humanity all over. It affects primarily the respiratory system, but is not limited to it, causing widespread involvement of many organ systems. The cases are still rising at an exponential rate and manifold trials are on to test different agents with the hope for potential limitation of spread and control of symptoms. Various classes of drugs have been tried; some with moderate success while many are yet to be proven to be of definite benefit. We have observed that the drugs used in dermatology practice are featured in more than a few of such studies. Here we wish to highlight the ones that we are familiar with, which has featured at some point, in the management of this very challenging pandemic. This article is protected by copyright. All rights reserved.
... Finally, our data suggest that male COVID-19 severity relates to hypogonadism, in common with co-morbidities that increase COVID-19 mortality, but also the opposite has been proposed (i.e., hypergonadism in men increasing the severity of COVID-19) [9]. Jones et al.'s [1] critique focuses around analytical rigor regarding subsidiary analysis in a small sample; consequently, it obfuscates the evidence for the former hypothesis. ...
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COVID-19 presents with mild symptoms in the majority of patients but in a minority it progresses to acute illness and hospitalization. Here we consider whether markers for prenatal sex hormones and postnatal stressors on developmental instability, i.e. digit ratios and their directional and unsigned asymmetries, are predictive of hospitalization. We focus on six ratios: 2D:3D; 2D:4D; 2D:5D; 3D:4D; 3D:5D; 4D:5D and compare hospitalized patient and control means for right, and left ratios, directional asymmetries (right–left) and unsigned asymmetries [|(right–left)|]. There were 54 patients and 100 controls. We found (i) patients differed in their digit ratios from controls (patients > controls) in all three ratios that included 5D (2D:5D, 3D:5D and 4D:5D) with small to medium effect sizes (d = 0.3 to 0.64), (ii) they did not differ in their directional asymmetries, and (iii) patients had greater |(right–left)| asymmetry than controls for 2D:4D (d = .74) , and all ratios that included 5D; 2D:5D (d = 0.66), 3D:5D (d = .79), 4D:5D (d = 0.47). The Composite Asymmetry of the two largest effects (2D:4D + 3D:5D) gave a patient and control difference with effect size d = 1.04. All patient versus control differences were independent of sex. We conclude that digit ratio patterns differ between patients and controls and this was most evident in ratios that included 5D. Large |(right–left)| asymmetries in the patients are likely to be a marker for postnatal stressors resulting in developmental perturbations and for potential severity of COVID-19.
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Globally, approximately 170,000 confirmed cases of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) have been reported, including an estimated 7,000 deaths in approximately 150 countries (1). On March 11, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic (2). Data from China have indicated that older adults, particularly those with serious underlying health conditions, are at higher risk for severe COVID-19-associated illness and death than are younger persons (3). Although the majority of reported COVID-19 cases in China were mild (81%), approximately 80% of deaths occurred among adults aged ≥60 years; only one (0.1%) death occurred in a person aged ≤19 years (3). In this report, COVID-19 cases in the United States that occurred during February 12-March 16, 2020 and severity of disease (hospitalization, admission to intensive care unit [ICU], and death) were analyzed by age group. As of March 16, a total of 4,226 COVID-19 cases in the United States had been reported to CDC, with multiple cases reported among older adults living in long-term care facilities (4). Overall, 31% of cases, 45% of hospitalizations, 53% of ICU admissions, and 80% of deaths associated with COVID-19 were among adults aged ≥65 years with the highest percentage of severe outcomes among persons aged ≥85 years. In contrast, no ICU admissions or deaths were reported among persons aged ≤19 years. Similar to reports from other countries, this finding suggests that the risk for serious disease and death from COVID-19 is higher in older age groups.
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Dr Li Wenliang, who lost his life to the novel coronavirus, SARS-CoV-2, became the face of the threat of SARS-CoV-2 to frontline workers, the clinicians taking care of patients. Li, 34, was an ophthalmologist at Wuhan Central Hospital. On 30th December, 2019, when the Wuhan municipal health service sent out an alert, he reportedly warned a closed group of ex-medical school classmates on the WeChat social media site of “Seven cases of severe acute respiratory syndrome (SARS) like illness with links with the Huanan Seafood Wholesale Market” at his hospital. He was among eight people reprimanded by security officers for “spreading rumours”. In a tragic turn of events, he subsequently contracted SARS-CoV-2 and, after a period in intensive care, died on the morning of Friday 7th February, 2020 (South China Morning Post, 2020). This case is a stark reminder of the risks of emerging disease outbreaks for healthcare workers (HCWs). Dr Li Wenliang’s name is added to the long list of HCW that were at the forefront of outbreaks of SARS, Ebola, MERS and now SARS-CoV-2. It is important to recognise that it was the clinicians in Wuhan who sounded the alarm about the emergence of SARS-CoV-2 which was rapidly identified after these clinicians sent samples to a reference laboratory for next generation sequencing (NGS) (Zhou et al., 2020).
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Background: Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods: We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results: The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions: During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.).
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Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks 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)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76–0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses. Genetic analysis of data from over 400,000 participants in the UK Biobank Study shows that circulating testosterone levels have sex-specific implications for cardiometabolic diseases and cancer outcomes.
Background Since December, 2019, an outbreak of coronavirus disease 2019 (COVID-19) has spread globally. Little is known about the epidemiological and clinical features of paediatric patients with COVID-19. Methods We retrospectively retrieved data for paediatric patients (aged 0–16 years) with confirmed COVID-19 from electronic medical records in three hospitals in Zhejiang, China. We recorded patients' epidemiological and clinical features. Findings From Jan 17 to March 1, 2020, 36 children (mean age 8·3 [SD 3·5] years) were identified to be infected with severe acute respiratory syndrome coronavirus 2. The route of transmission was by close contact with family members (32 [89%]) or a history of exposure to the epidemic area (12 [33%]); eight (22%) patients had both exposures. 19 (53%) patients had moderate clinical type with pneumonia; 17 (47%) had mild clinical type and either were asymptomatic (ten [28%]) or had acute upper respiratory symptoms (seven [19%]). Common symptoms on admission were fever (13 [36%]) and dry cough (seven [19%]). Of those with fever, four (11%) had a body temperature of 38·5°C or higher, and nine (25%) had a body temperature of 37·5–38·5°C. Typical abnormal laboratory findings were elevated creatine kinase MB (11 [31%]), decreased lymphocytes (11 [31%]), leucopenia (seven [19%]), and elevated procalcitonin (six [17%]). Besides radiographic presentations, variables that were associated significantly with severity of COVID-19 were decreased lymphocytes, elevated body temperature, and high levels of procalcitonin, D-dimer, and creatine kinase MB. All children received interferon alfa by aerosolisation twice a day, 14 (39%) received lopinavir–ritonavir syrup twice a day, and six (17%) needed oxygen inhalation. Mean time in hospital was 14 (SD 3) days. By Feb 28, 2020, all patients were cured. Interpretation Although all paediatric patients in our cohort had mild or moderate type of COVID-19, the large proportion of asymptomatic children indicates the difficulty in identifying paediatric patients who do not have clear epidemiological information, leading to a dangerous situation in community-acquired infections. Funding Ningbo Clinical Research Center for Children's Health and Diseases, Ningbo Reproductive Medicine Centre, and Key Scientific and Technological Innovation Projects of Wenzhou.
The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.