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R E V I E W Open Access
Impact of sex and gender on COVID-19
outcomes in Europe
Catherine Gebhard
1,2,3*†
, Vera Regitz-Zagrosek
4,5,6†
, Hannelore K. Neuhauser
6,7
, Rosemary Morgan
8
and
Sabra L. Klein
9
Abstract
Background: Emerging evidence from China suggests that coronavirus disease 2019 (COVID-19) is deadlier for
infected men than women with a 2.8% fatality rate being reported in Chinese men versus 1.7% in women. Further,
sex-disaggregated data for COVID-19 in several European countries show a similar number of cases between the
sexes, but more severe outcomes in aged men. Case fatality is highest in men with pre-existing cardiovascular
conditions. The mechanisms accounting for the reduced case fatality rate in women are currently unclear but may
offer potential to develop novel risk stratification tools and therapeutic options for women and men.
Content: The present review summarizes latest clinical and epidemiological evidence for gender and sex
differences in COVID-19 from Europe and China. We discuss potential sex-specific mechanisms modulating the
course of disease, such as hormone-regulated expression of genes encoding for the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV2) entry receptors angiotensin converting enzyme (ACE) 2 receptor and TMPRSS2
as well as sex hormone-driven innate and adaptive immune responses and immunoaging. Finally, we elucidate the
impact of gender-specific lifestyle, health behavior, psychological stress, and socioeconomic conditions on COVID-
19 and discuss sex specific aspects of antiviral therapies.
Conclusion: The sex and gender disparities observed in COVID-19 vulnerability emphasize the need to better
understand the impact of sex and gender on incidence and case fatality of the disease and to tailor treatment
according to sex and gender. The ongoing and planned prophylactic and therapeutic treatment studies must
include prospective sex- and gender-sensitive analyses.
Keywords: Gender, Sex, COVID-19, Renin angiotensin aldosterone system, Immune system
Introduction
In December 2019, a novel β-coronavirus, now desig-
nated SARS-CoV2 (severe acute respiratory syndrome
coronavirus 2), was identified as the cause of an out-
break of acute respiratory illness in Wuhan City, China
[1]. SARS-CoV2 causes severe respiratory disease,
termed coronavirus disease 2019 (COVID-19), which
represents its most frequent lethal complication. Since
its outbreak, SARS-CoV2 has spread to 196 countries
and has been declared a pandemic by the World Health
Organization (WHO) on March 11, 2020 [2,3]. It has
caused over 2 million confirmed infections with over
130,000 deaths worldwide (as of April 15, 2020), of
which two-thirds have occurred in Europe [4]. To date,
no specific antiviral treatment for SARS-CoV2 exists,
but a number of investigational agents are currently be-
ing explored including remdesivir, lopinavir-ritonavir, a
combined protease inhibitor, chloroquine/hydroxychlor-
oquine, colchicine, and tocilizumab, an IL-6 inhibitor
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* Correspondence: Catherine.gebhard@usz.ch
†
Catherine Gebhard and Vera Regitz-Zagrosek contributed equally to this
work.
1
Department of Nuclear Medicine, University Hospital Zurich, Raemistrasse
100, 8091 Zurich, Switzerland
2
Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
Full list of author information is available at the end of the article
Gebhard et al. Biology of Sex Differences (2020) 11:29
https://doi.org/10.1186/s13293-020-00304-9
[5]. The worldwide case fatality rate of 3.4% of COVID-
19 now exceeds that from seasonal influenza [2]. Death
results from acute respiratory distress syndrome (ARDS),
acute respiratory failure, coagulopathy, septic shock, and
metabolic acidosis [6]. Cardiovascular complications of
COVID-19 comprise arrhythmias, acute cardiac injury,
and shock, and have been reported in 7–17% of hospital-
ized patients [7]. In Italy, the estimated case fatality rate
was 7.2% [8], while it was 0.9% in South Korea [3] and
2.3% in China [6]. Case fatality is highest in those aged >
80 years (14.8% in China, 20.2% in Italy) and in patients
with pre-existing conditions including cardiovascular
disease, diabetes mellitus, chronic respiratory disease,
hypertension, and cancer [6,9]. Among all comorbidi-
ties, cardiovascular disease in the elderly was most con-
sistently associated with adverse outcomes, as a case
fatality rate of 10.5% has been reported in this high-risk
population [6].
Sex differences in COVID-19 epidemiology and case
fatality
First reports from China have pointed to a sex imbal-
ance with regard to detected cases and case fatality rate
of COVID-19 [1,10,11]. However, to date only few re-
ports have addressed the sex disproportion in COVID-
19 incidence and disease course and a thorough analysis
of underlying causes is currently lacking [12–15]. As the
disease has spread across multiple continents, the Global
Health 50/50 research initiative presented an impressive
overview of sex-disaggregated data from countries
worldwide clearly demonstrating similar numbers of
cases in women and men, but an increased case fatality
in men [16] (Fig. 1). Nevertheless, sex-disaggregated data
are still not provided by all countries, the interaction of
sex and age is usually not visible in the public databases,
and number of cases and case fatality vary significantly
by region. To obtain a detailed European view and to
cover these aspects, we collected latest epidemiological
data (as of April 1st) on confirmed COVID-19 cases in
Italy, China, Spain, France, Germany, and Switzerland
[17–22] across multiple disease metrics including re-
cently published hospitalization and intensive care (ICU)
admission data. Similar to global statistics, these reports
show no major sex differences in the absolute number of
confirmed COVID-19 cases in those countries where
sex-disaggregated data were available (Fig. 2). However,
equal absolute numbers of cases in women and men
may point towards a higher incidence in men in the
older age groups (i.e., proportions of COVID-19 diag-
nosed older men among men in that age group) since
older men are fewer in absolute numbers than older
women due to their shorter life expectancy. In fact, re-
ports from Switzerland and Germany have recently re-
ported incidence rates (cases per 100,000 inhabitants by
age and sex), which confirm an increased disease inci-
dence in men > 60 years, [21,22]. In detail, the disease
incidence in men per 100,000 Swiss inhabitants in the
age groups of 60–69 years, 70–79 years, and 80+ years
was 267, 281, and 477, respectively, as of March 30. The
numbers reported in men exceeded the ones reported in
Fig. 1 Sex-disaggregated data of confirmed COVID-19 cases and deaths provided by Global Health 50%50 data tracker as of April 2, 2020 [16]
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 2 of 13
women by 74, 87, and 108 per 100,000 Swiss inhabitants,
respectively. In Germany, relative differences between
men and women were similar to Switzerland, but at a
lower level, with the incidence in Germany being one-
third of that in Switzerland. It is notable, however, that
the number of confirmed cases and therefore also the in-
cidence depends largely on testing strategy in countries
and regions.
Novel data on disease course and severity show 50%
more hospitalized men than women (Fig. 2). Notably, al-
though the overall number of confirmed COVID-19
cases across all age groups is currently sex balanced in
Switzerland, the hospitalizations in men exceed the one
observed in women by 1.5-fold. A similar gender distri-
bution in hospitalization rates is observed in France.
This imbalance supports a higher susceptibility of men
to develop severe respiratory disease following SARS-
CoV2 infection, leading to more hospital admissions.
While the number of ICU admissions of men and
women are currently unknown in Switzerland, in France,
and in the Lombardy region (Italy), the number of men
receiving ICU care is 3-fold and 4-fold higher than the
number of women [23]. The latter might be indicative of
gender differences in COVID-19 disease severity; how-
ever, gender inequity in ICU admission policies may also
play a role.
Significant differences in the male to female COVID-
19 case fatality ratio can be observed between European
countries. The latter may also reflect the age-sex mix of
cases by country as well as national testing strategies, be-
sides case fatality. Nevertheless, case fatality rates re-
ported in China, Italy, Spain, France, Germany, and
Switzerland are relatively homogenous and range be-
tween 1.7–1.8. This supports the view that a consistent
biological phenomenon is operating, accounting for the
higher case fatality in men, independent of country-
specific demographics and testing strategies (Fig. 2)[17–
19,21,22]. In addition, pooled data comprising 227,219
confirmed cases and 14,364 deaths suggest that the male
to female case fatality ratio is consistently elevated
through all age groups and may even be most pro-
nounced at middle age (Fig. 3). The latter is a novel ob-
servation which further supports the notion that age as
well as gender-specific behavior and/or biological vari-
ables interact in COVID-19 disease vulnerability. How-
ever, more data are needed to confirm an interaction
between age and sex in COVID-19 case fatality.
Sex differences in ACE2 and TMPRSS2 regulation
To enter cells, SARS-Cov-2 binds to the angiotensin
converting enzyme (ACE) 2 receptor and the cellular
serine protease TMPRSS2 for priming [24] (Fig. 5).
ACE2 is a membrane-bound protein and is expressed in
multiple tissues including the cardiovascular system, adi-
pose tissue, gut and kidneys, the central nervous system,
and in the lungs [25]. The cell-associated form of ACE2
is required for SARS-CoV virus entry into target cells
[26]. ACE2 is cleared from the cells by the
Fig. 2 Male to female ratios of COVID-19 cases, hospitalizations, intensive care unit (ICU) admissions, deaths, and case-fatality rates in European
countries and China as of April 2, 2020. *absolute numbers are provided. Sex-disaggregated data were not available for all indicators
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 3 of 13
metalloproteases ADAM10 and ADAM17 [26,27]. Some
reports indicate that circulating levels of ACE2 are
higher in healthy and diabetic men as well as in men
with renal disease as compared to women [28]. Others
found no sex difference but reported higher ACE2
serum activity in older compared to younger women
[29]. In patients with type 1 diabetes, circulating ACE2
activity increases with increasing vascular tone and in
the presence of microvascular or macrovascular athero-
sclerotic disease [30]. Soluble ACE2 is enzymatically ac-
tive and has modest inhibitory effects on viral infection
efficiency [31]. However, these data are not yet coherent
and the link between circulating ACE2 and COVID-19
is not clear.
ACE2 plays a crucial role in the renin angiotensin al-
dosterone system (RAAS) as it opposes the vasocon-
strictor actions of angiotensin II by converting
angiotensin II to vasodilatory angiotensin 1–7 in differ-
ent organs. ACE2 regulates the cellular biology of cardi-
omyocytes, cardiac fibroblasts, and coronary endothelial
cells in both heart failure with reduced ejection fraction
(HFrEF) and heart failure with preserved ejection frac-
tion (HFpEF) models and after experimental myocardial
infarction [32,33]. Therefore, increasing ACE2 activity
was considered a potential therapeutic option for
COVID-19 [34]. However, a previous report suggests
that high protein expression of ACE2 receptor in specific
organs was associated with organ failure in patients in-
fected by SARS in 2002/2003 [35], while 35% of myocar-
dial tissue samples of patients who died from SARS
showed a reduced myocardial ACE2 protein expression
along with viral RNA [36]. A loss of ACE2 function
through endocytosis and activation of proteolytic cleav-
age following SARS-CoV-2 binding has recently been
described and could reconcile these apparently contra-
dictory findings [25].
In the lung, ACE2 is primarily expressed in bronchial
transient secretory cells or type II alveolar cells [37]. Ex-
perimental evidence derived from murine and rat
models suggests a protective role of ACE2 activators in
vascular remodeling during pulmonary hypertension, in
allergic airway inflammation associated with asthma, and
in the reduction of pulmonary fibrosis [38,39]. Further,
ACE2 activation improved pulmonary endothelial func-
tion in a rat model of pulmonary hypertension via the
endothelial nitric oxide synthase (eNOS) pathway and
seems to play an important role in smoking-induced
lung injury [40]. Indeed, the latter was associated with a
significant reduction of ACE2 expression in lung tissue
which was reversed by Losartan treatment [41]. These
preclinical studies suggest a protective role and a poten-
tial therapeutic use of ACE2 in a variety of pulmonary
diseases. It is however currently unclear whether the role
of ACE2 in pulmonary pathologies differs by sex. In
addition to the above mentioned studies, ACE inhibitors
and angiotensin receptor blockers (ARBs) have been re-
ported to upregulate ACE2 expression in different or-
gans in humans [42,43] and experimental animals [44],
whereas no effect of ACE inhibitors or ARBs on ACE2
activity was found in other reports [33]. The interaction
between COVID-19 and ACE inhibitors or ARBs in pa-
tients with heart disease was recently reviewed [45]. This
Fig. 3 Male predominance in COVID-19 case fatality (deaths divided by confirmed cases) in Italy, Spain, Germany, and Switzerland by age. A male
to female mortality ratio of 1 would reflect gender balance, the red bars reflect male predominance. Pooled data from Italy as of March 30, 2020,
Spain as of March 31, 2020, Germany as of April 1, 2020, and Switzerland as of March 31, 2020
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 4 of 13
topic is out of the scope of the present review which fo-
cuses on sex differences.
There is increasing evidence that sex and sex hor-
mones affect many components of the circulating as well
as tissue-based RAAS including ACE2 [46–50] (Fig. 4).
Downregulation of angiotensin II receptor type 1
(AT1R) by estrogens, and regulation of renin activity by
estrogens have been described and reviewed elsewhere
[51,52]. More recently, it was shown that estrogen mod-
ulates the local RAAS in human atrial myocardium via
downregulation of ACE and simultaneous upregulation
of ACE2, AT2R, and MAS expression levels [53]. The
ACE2/Ang1-7/Mas receptor axis appears to be of greater
relevance in women than in men [47]. Indeed, genes
coding for ACE2 and angiotensin II receptor 2 (AT2R)
are located on the X chromosome suggesting a potential
for higher expression in women [54]. Nevertheless, re-
ports from a number of preclinical studies agree that
ACE2 is frequently higher expressed in males than in fe-
males, mainly under pathological conditions [47,50,55].
In addition to sex chromosome complement, sex hor-
mones promote opposite effects on ACE and ACE2 ac-
tivity, cardiac hypertrophy, and contractility in
spontaneously hypertensive rats [56]. Ovariectomy led to
increased ACE2 activity in females, whereas in males,
orchiectomy decreased ACE2 activity. In agreement with
these data, ovariectomy increased ACE2 expression in
the female kidney, and adipose tissue, and estradiol re-
placement reduced ACE2 expression [46]. Thus, testos-
terone seems to maintain high ACE2 levels in the heart
and kidney, whereas estrogen reduces ACE2 expression
in these organs. Based on these data, we must assume
that a significant interaction between sex hormones and
ACE2 expression exists.
In humans, several clinical trials highlight the rele-
vance of sex differences in the RAAS. In fact, a recent
prospective cohort study indicates that women require
lower doses of ACE inhibitors for heart failure treatment
than men [57]. Also, the neprilysin (NEP) inhibitor sacu-
bitril, which degrades angiotensin peptides, in combin-
ation with valsartan, has recently been shown to exert
beneficial effects in women with HFpEF, but less so in
men [58]. Unfortunately, specific mechanisms account-
ing for this difference have not been reported in these
studies. A higher tissue expression of ACE2 has been ob-
served in Asian men as compared to women [28,59],
while in our own unpublished investigation in tissue
samples from patients with aortic valve stenosis, ACE2
was upregulated 4–5 fold in the myocardium of men as
compared to their female counterparts. In contrast, no
Fig. 4 Estrogen and sex regulate components of the renin angiotensin aldosterone system (RAAS). Estrogen-regulated pathways are depicted in
green. AT2R angiotensin II type 2 receptor, ACE2 angiotensin converting enzyme 2, NEP neutral endopeptidase neprilysin
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 5 of 13
sex difference in ACE2 expression was seen in control
hearts [60]. Whether these sex differences in ACE2 regu-
lation are of clinical relevance remains to be determined.
The second protein, necessary for SARS-CoV2 inva-
sion into cells, the cell-surface serine protease TMPRSS2
is predominantly expressed in prostate epithelium, in
high-grade prostate cancers, and in the majority of hu-
man prostate cancer metastases [61,62]. Although
TMPRSS2 is expressed several fold higher in the pros-
tate relative to any other human tissue, the serine prote-
ase has also been detected in airway epithelia where its
normal physiologic function remains unknown [63].
TMPRSS2 transcription is regulated by androgenic li-
gands and an androgen receptor binding element in the
promoter [64] (Fig. 5). Notably, recurrent gene fusions
of the 5′untranslated region of TMPRSS2 to the tran-
scription factor ERG is the most frequent genomic alter-
ation in early- and late-stage prostate cancer and results
in overexpression of ERG. The latter is present in both
early- and late-stage prostate cancer [64]. However, it is
currently unclear under which conditions the fusion pro-
tein is generated, whether TMPRSS2 is also regulated by
estrogen, and whether it plays a role in COVID-19. The
involvement of TMPRSS2 in viral S protein priming
might explain, at least in part, the higher case fatality
seen in males affected by COVID-19. Accordingly, a
TMPRSS2 inhibitor has recently been shown to block
entry of the virus in vitro and might become a thera-
peutic strategy for antiviral intervention [24]. Whether
previous prostate cancer and anti-androgenic treatment
might affect virus entry and the course of disease is cur-
rently unknown [64].
Sex differences in immune responses to viruses
Females and males differ in their susceptibility and re-
sponse to viral infections, leading to sex differences in
incidence and disease severity [65]. For infectious dis-
eases caused by viruses, there are numerous and diverse
ways in which sex and gender can impact differential
susceptibility between males and females. For example,
Fig. 5 Sexual dimorphism in TMPRSS2-mediated SARS-CoV2 host cell entry. Androgen receptors (ARs) are activated via heat shock proteins (HSPs)
release in response to changes in intracellular testosterone concentration. ARs are then phosphorylated and translocated as homodimers into the
nucleus, prompting transcriptional activation of TMPRSS2 and translation of the TMPRSS2 protein [149]. At the cell membrane, TMPRSS2 facilitates
viral entry and spreads into the host cell by activating the spike proteins [24]
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 6 of 13
human studies reveal that females have over 40% less
human immunodeficiency virus (HIV) RNA in circula-
tion than males. Despite having less circulating HIV
RNA than males, females who are matched with males
on their HIV RNA loads have a 1.6-fold higher risk of
developing AIDS [66]. Although exposure to influenza A
viruses is often higher in males, fatality following expos-
ure to pathogenic influenza A viruses is reportedly
higher in females [67]. In contrast, the prevalence of
serum hepatitis B virus (HBV) surface antigen, HBV
DNA titers, and development of hepatocellular carcin-
oma is higher in males than females [68–70].
The innate recognition and response to viruses as well
as downstream adaptive immune responses during viral
infections differ between females and males. The num-
ber and activity of innate immune cells, including mono-
cytes, macrophages, and dendritic cells (DCs) as well as
inflammatory immune responses in general are higher in
females than in males [71–73]. Toll-like receptor (TLR)
7 is a pattern recognition receptor in the endosomes of
several immune cells, including plasmacytoid DCs and B
cells, and is used to detect single stranded RNA viruses,
including coronaviruses. The TLR7 gene, encoded on
the X chromosome, may escape X inactivation resulting
in higher expression levels of TLR7 in females when
compared to males [74–76]. Exposure of peripheral
blood mononuclear cells (PBMCs) to TLR7 ligands
in vitro causes higher production of interferon-α(IFNα)
in cells from females than from males [77], and plasma-
cytoid DCs (pDCs) from females and female mice have
higher basal levels of IFN regulatory factor 5 (IRF5) and
IFNαproduction following TLR7 ligand stimulation
[78]. Immune responses to viruses can vary with changes
in sex hormone concentrations naturally observed over
the menstrual cycle, following contraception, after
menopause and during hormone replacement therapy
(HRT) as well as during pregnancy [79].
With regard to adaptive immune responses, females
generally exhibit greater humoral and cell-mediated im-
mune responses to antigenic stimulation, vaccination,
and infection than do males [80]. Both basal levels of im-
munoglobulin [81] as well as antibody responses are
consistently higher in females than in males [82]. In
humans, global analysis of B cell gene expression signa-
tures reveals that the majority of genes differentially
expressed between the sexes are significantly upregu-
lated in B cells from adult females compared with males
[83]. Clinical studies reveal that males have lower CD3+
and CD4+ cell counts, CD4+:CD8+ cell ratios, and
helper T cell type 1 (Th1) responses than females [84–
87]. Females also exhibit higher cytotoxic T cell activity
along with upregulated expression of antiviral and pro-
inflammatory genes, many of which have estrogen re-
sponse elements in their promoters [88].
Sex steroids, particularly testosterone (T), estradiol
(E2), and progesterone (P4), influence the functioning of
immune cells. Sex steroids alter the functioning of im-
mune cells by binding to specific receptors, which are
expressed in various lymphoid tissue cells as well as in
circulating lymphocytes, macrophages, and dendritic
cells [89]. The binding of sex steroids to their respective
steroid receptors directly influences cell signaling path-
ways, including NF-κB, cJun, and interferon regulatory
factor (IRF) 1, resulting in differential production of cy-
tokines and chemokines [89]. Although direct effects of
gonadal steroids cause many sex differences in immune
function, some sex differences might be caused by the
inherent imbalance in the expression of genes encoded
on the X and Y chromosomes [90]. Polymorphisms or
variability in sex chromosomal genes as well as in auto-
somal genes that encode for immunological proteins can
also contribute to sex differences in immune responses
[91].
Sex differences in immune response in cardiac tissues
also depend on age. We have recently shown that fe-
males develop stronger chronic immune reactions in the
myocardium with old age [92]. Aging is associated with
the development of a chronic low-grade inflammatory
phenotype (CLIP) [93]. Such CLIP may be induced by
chronic viral infections, among others. Cellular senes-
cence may also contribute to CLIP as senescent cells cir-
culate in the tissues through the body. They secrete a
variety of pro-inflammatory mediators, stimulating CLIP.
Furthermore, factors as smoking, decreased production
of sex steroids, and accumulation of adipose tissue may
also contribute to CLIP.
Gender-related risk factors and impact
When considering differentials in incidence and case fatal-
ity between males and females, we must also consider
how sex intersects with gender to influence vulnerability.
Gender is defined as the social and cultural norms, roles,
attributes, and behaviors that a society considers appropri-
ate for men and women or boys and girls [94]. Evidence
suggests that the current COVID-19 pandemic has both
primary and secondary effects related to sex and gender.
Primary effects include differences between males/men
and females/women in incidence and case fatality, while
secondary effects include differences in social and eco-
nomic consequences as a result of the pandemic, includ-
ing risk of domestic violence [95,96], economic and job
insecurity, and increased domestic workload [15].
Preliminary data indicate an association between co-
morbidities, such as chronic lung disease, hypertension,
and cardiovascular disease, and severity of COVID-19
[16]. Worldwide, these morbidities are higher among
men than women [97], except for older age groups. Gen-
der differences in risk behaviors, such as smoking and
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 7 of 13
drinking, may be contributing to the gender gaps in
mortality of such non-communicable diseases [13].
Smoking and drinking rates are higher among men than
women worldwide. Such behaviors are associated with
the risk of developing comorbidities [16]. These behav-
iors are linked to gender norms related to what is con-
sidered appropriate behaviors and activities for men and
women [98]. Other gendered norms and behaviors
which may be contributing to a higher incidence among
men include lower rates of hand washing, which is a rec-
ognized preventative measure, and delayed healthcare
seeking [16]. Evidence from China suggests that patients
whose diagnoses were delayed were at greater risk of
dying [99]. In this regard, greater system delays between
onset of symptoms and initiation of treatment have been
described in women with cardiovascular disease [100];
however, no data on prehospital delays in COVID-19 are
currently available. Thus, it is currently unknown
whether potential gender differences in prehospital de-
lays impose disadvantages on women. Other gendered
differences which place women and men at differential
risk of infection and/or mortality include rejection of so-
cial isolation, social obligations, psychological stress, low
quality of life, and low socioeconomic status among
COVID-19 [13]. A careful analysis of a patient’s history
including traditional cardiovascular risk factors, socio-
economic status, menopausal status, age at menopause,
number of pregnancies, pregnancy-related complica-
tions, fertility treatments, postmenopausal HRT, hormo-
nal contraception, history of breast or prostate cancer,
and aromatase inhibitors/anti-androgenic treatments will
be essential to discover mechanisms accounting for the
gender disparities in COVID-19.
Women’s roles as caregivers—both within the health
system and at home—may place them at increased risk
of infection. Approximately 70% of health and social
care workforce worldwide are women [101], including
frontline healthcare workers. Women are also more
likely to care for children or other relatives who are ill
[15]. Overall, more research is needed to understand
how sex and gender, and the intersection of sex and gen-
der, is causing differential outcomes and effects related
to COVID-19 among and between men and women. In
particular, there is a need to evaluate the influence of
such gender variables on disease manifestation and
outcomes.
Sex differences in COVID-19 treatment approaches
Vaccines are the best prophylactic treatment for infec-
tious diseases as they provide immunity and protection
prior to infection. Sex and gender impact vaccine ac-
ceptance, responses, and outcomes. Females are often
less likely to accept vaccines, but once vaccinated, de-
velop higher antibody responses (i.e., primary correlate
of protection) and report more adverse reactions to vac-
cines than males (Table 1)[80]. For example, after vac-
cination against influenza, yellow fever, rubella, measles,
mumps, hepatitis A and B, herpes simplex 2, rabies,
smallpox, and dengue viruses, protective antibody re-
sponses are twice as high in adult females as compared
with males [80]. Data from inactivated influenza vaccines
indicate that adult (18–45 years of age) females develop
greater IL-6 and antibody responses than males, with di-
minished differences between the sexes among aged in-
dividuals (65+ years of age) [128]. Reduced male-female
differences in immune responses to the monovalent
Table 1 Sex differences in adverse reactions, immune responses, and efficacy of vaccines and antiviral drugs in humans
Virus Antiviral drug/vaccine Sex-specific
features
Comments References
HIV HAART M < F CD4+ T cell count, adverse reactions, fat accumulation, drug
concentration, virus clearance, hepatitis
[102–108]
HAART M > F Fat loss, survival [103,109]
HSV-2 HSV-2 gD vaccine M < F Humoral immune responses, cell-mediated immune responses, vaccine
efficacy
[110–112]
Acyclovir M < F Frequency of prescription, adverse reaction [113,114]
Acyclovir M > F Reduction of virus shedding [114]
HBV HBV vaccine M < F Humoral immune responses [115–118]
HCV Pegylated interferon
alpha/ribavirin
M < F Adverse reaction, sustained virologic response
1
[119–121]
Seasonal influenza
viruses
TIV vaccine M < F Humoral immune responses, adverse reactions [122–125]
Oseltamivir M < F Drug clearance and metabolism
2
[126]
Oseltamivir M > F Alleviation of symptoms, reduction of viral load [127]
Zanamivir M = F Alleviation of symptoms, reduction of viral load [127]
HAART highly active antiretroviral therapy, HBV hepatitis B virus, HCV hepatitis C virus, HIV human immunodeficiency virus, HSV herpes simplex virus, TIV trivalent
inactivated influenza virus.
1
premenopausal females only,
2
tested in neonates only
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 8 of 13
2009 H1N1 vaccine among aged individuals is partly due
to reproductive senescence in females, in which higher
circulating estradiol concentrations in females are
associated with greater antibody responses to the vaccine
[128].
For treatment of COVID-19, a number of investiga-
tional agents are currently being explored including
remdesivir, lopinavir-ritonavir, a combined protease in-
hibitor, chloroquine/hydroxychloroquine, colchicine, and
tocilizumab, an IL-6 inhibitor [5]. Although some of
these compounds have shown promise in inhibiting the
growth of SARS-CoV2 in vitro [5,129–131,132], their
“off-label”use carries the risk of adverse side effects such
as cardiac arrhythmias and sudden cardiac death [133,
134]. In particular chloroquine and hydroxychloroquine,
both antimalarial agents inhibiting the cell entry of
SARS-CoV2 by under-glycosylation of ACE2 receptors
[129,130], are known to trigger life-threatening poly-
morphic ventricular tachycardia (torsades de pointes) by
prolonging the heart rate-corrected QT (QTc) interval
[134,135]. Previous reports indicate that women are
more prone to develop drug-induced torsades de pointes
than men, with 65–75% of drug-induced torsades de
pointes occurring in women [136]. Indeed, there are
substantial sex differences in the electrocardiographic
pattern of ventricular repolarization with a longer QTc
interval at baseline being observed in women [48,136,
137]. Protective effects of testosterone have been sug-
gested to account for the shorter QTc interval and the
reduced incidence of drug-induced torsades de pointes
in men. However, mechanisms underlying these differ-
ences are not fully understood. In addition, experimental
and clinical studies have shown that chloroquine exerts
different effects on adrenocortical function in female
and male rats [138] and depresses testosterone secretion
and sperm count in men [139]. The latter is of particular
interest in the treatment of COVID-19 as the expression
of TMPRSS2, a protein that primes SARS-CoV-2 entry
into cells, is upregulated by androgens [140]. The latter
has been suggested to account for the higher mortality
seen in men affected by COVID-19. However, whether
anti-androgenic treatment might affect virus entry and
the course of disease is currently unknown.
Further, there is evidence that women encounter more
often adverse drug reactions to antiviral treatment than
men (Table 1). In addition, pharmacokinetics and treat-
ment responses to antiretroviral therapy with ritonavir
and lopinavir differ between males and females [141]. In
fact, higher plasma concentrations of ritonavir and a
higher total cholesterol:high-density lipoprotein (HDL)
ratio have been reported in girls [141,142], while an ata-
zanavir plus ritonavir regimen was associated with a
higher risk of virologic failure in women as compared to
men [131].
The current off-label use of anti-inflammatory drugs,
such as colchicine, for the reduction of excessive inflam-
mation caused by SARS-CoV2 is also notable. The COL-
CORONA trial has just started recruiting patients with
COVID-19 and will determine whether short-term treat-
ment with colchicine reduces the rate of death and lung
complications related to COVID-19 (https://clinical-
trials.gov/ct2/show/NCT04322682). The drug has re-
cently regained popularity when it was shown that
colchicine reduced the risk of ischemic cardiovascular
events in patients with a recent myocardial infarction
[143]. However, while the primary efficacy composite
endpoint was reduced by colchicine in the total cohort
and in men, a subgroup analysis pointed to a lower effi-
cacy in women [143]. Also, previous experimental work
in rats reports a higher acute oral toxicity of colchicine
in females as compared to males with female rats being
two times more susceptible to the lethal effects of col-
chicine than male rats [144]. Thus, a sex-specific analysis
in the COLCORONA trial will be essential in order to
take these differences into account.
Taken together, these data emphasize the importance
to consider the effect of age, reproductive status, and ex-
ogenous hormonal manipulation when antiviral and
other treatment strategies are applied to COVID-19
patients.
Conclusion
The sex and gender disparities observed in COVID-19
vulnerability emphasize the need to understand the im-
pact of sex and gender on incidence and case fatality of
the disease and to tailor treatment according to sex and
gender. Experiences from past outbreaks and pandemics
have clearly shown the importance of incorporating a
sex and gender analysis into preparedness and response
efforts of health interventions [67,145–148]. Policies
and public health efforts, however, have not yet ad-
dressed the gendered impacts of disease epidemics, out-
breaks, or pandemics. Some countries have not
disaggregated data by sex and age the way other coun-
tries have. In conclusion, governments in all countries
should disaggregate and analyze data for sex and age dif-
ferences. Furthermore, as prophylactic and therapeutic
treatment studies begin, inclusion of sex and gender
analyses in their protocols must occur.
Abbreviations
ARs: Androgen receptors; ARDS: Acute respiratory distress syndrome;
ACE: Angiotensin converting enzyme 2; ARBs: Angiotensin receptor blockers;
AT2R: Angiotensin II receptor; CLIP: Chronic low-grade inflammatory pheno-
type; COVID-19: Coronavirus disease 2019; DCs: Dendritic cells; HAART: Highly
active antiretroviral therapy; HFpEF: Heart failure with preserved ejection
fraction; QTc: Heart rate-corrected QT interval; HSPs: Heat shock proteins;
Th1: Helper T cell type 1; HBV: Hepatitis B virus; HCV: Hepatitis C virus;
HSV: Herpes simplex virus; HDL: High density lipoprotein; HIV: Human
immunodeficiency virus; ICU: Intensive care unit; NEP: Neutral endopeptidase;
HRT: Postmenopausal hormone replacement therapy; SARS-CoV2: Severe
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 9 of 13
acute respiratory syndrome coronavirus 2; TIV: Trivalent inactivated influenza
virus; TLR: Toll-like receptor; RAAS: Renin angiotensin aldosterone system;
WHO: World Health Organization
Acknowledgements
We thank Dr. Susan Bengs and Dr. Ahmed Haider for their help in preparing
the figures of this manuscript and Ms Anna Metterhausen for helping with
the literature search. We thank Ms Michaela Diercke for providing
epidemiological data from Germany. We thank Prof. Beatrice Beck Schimmer
for her continued support of gender-specific medicine at the University of
Zurich.
Authors’contributions
HKN analyzed and interpreted the patient data regarding COVID-19 case fa-
tality and mortality, CG and VRZ were major contributors in designing and
writing the manuscript, SLK wrote the paragraphs on sex differences in anti-
viral treatment and immune responses, and RM wrote the paragraph on
gender-related risk factors and impact. All authors read and approved the
final manuscript.
Funding
CG was supported by grants from the Swiss National Science Foundation
(SNSF), the Olga Mayenfisch Foundation, Switzerland, the OPO Foundation,
Switzerland, the Novartis Foundation, Switzerland, the Swissheart
Foundation, the Helmut Horten Foundation, Switzerland, the EMDO
Foundation, Switzerland, the Iten-Kohaut Foundation, Switzerland, and the
University Hospital Zurich Foundation. SK and RM were suppored by the
NIH/ORWH/NIA Specialized Center of Research Excellence in Sex Differences
(U54AG062333). VRZ is funded by EU (Gender Academy 824585), BMG
(GeSeMS, ZMVL1-2520FSB431) and BMBF (DZHK-Gender 81Z2100201;
Gendage 01GL1716B).
Availability of data and materials
Not applicable
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Competing interests
None declared
Author details
1
Department of Nuclear Medicine, University Hospital Zurich, Raemistrasse
100, 8091 Zurich, Switzerland.
2
Center for Molecular Cardiology, University of
Zurich, Schlieren, Switzerland.
3
Department of Internal Medicine II, Medical
University of Vienna, Vienna, Austria.
4
University of Zurich, Zurich,
Switzerland.
5
Charité, Universitätsmedizin Berlin, Berlin, Germany.
6
DZHK
(German Centre for Cardiovascular Research), partner site Berlin, Berlin,
Germany.
7
Robert Koch Institute, Berlin, Germany.
8
Department of
International Health, The Johns Hopkins Bloomberg School of Public Health,
Baltimore, Maryland, USA.
9
W. Harry Feinstone Department of Molecular
Microbiology and Immunology, The Johns Hopkins Bloomberg School of
Public Health, Baltimore, Maryland, USA.
Received: 6 April 2020 Accepted: 24 April 2020
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