| |

Received: 25 January 2021    Revised: 8 March 2021    Accepted: 16 March 2021

DOI: 10.1111/andr.13003

ORIGINAL ARTICLE

“Mask up to keep it up”: Preliminary evidence of the

association between erectile dysfunction and COVID-19

Andrea Sansone1  | Daniele Mollaioli1  | Giacomo Ciocca2  | Elena Colonnello1  |

Erika Limoncin1 | Giancarlo Balercia3  | Emmanuele A. Jannini1

1
Endocrinology and Medical Sexology
(ENDOSEX, Department of Systems
Medicine, University of Rome Tor Vergata,
Roma, Italy
2
Department of Dynamic and Clinical
Psychology, Health Studies "Sapienza"
University of Rome, Rome, Italy
3
Division of Endocrinology, Department
of Clinical and Molecular Sciences,
Polytechnic University of Marche, Ancona,
Italy
Correspondence
Emmanuele A. Jannini, Endocrinology
and Medical Sexology (ENDOSEX),
Department of Systems Medicine,
University of Rome Tor Vergata, Roma, via
Montpellier 1, 00133 Rome, Italy.
Email: eajannini@gmail.com
Funding information
This work was carried out within the
framework of an Italian Ministry of
University project and was partly
supported by the PRIN 2017S9KTNE_002
grant by the Italian Ministry of Education,
University and Research.
Abstract
Background: Erectile dysfunction (ED), as the hallmark of endothelial dysfunction,
could be a short- or long-term complication of COVID-19. Additionally, being ED a
clinical marker and predictor of non-communicable chronic diseases, particularly
cardiovascular, subjects with ED could potentially have a higher risk of contracting
COVID-19.
Objectives: To investigate the prevalence of ED among subjects with a reported diag-
nosis of COVID-19 and to measure the association of COVID-19 and ED.
Materials and methods: We reviewed data from the Sex@COVID online survey (per-
formed between April 7 and May 4, 2020, in Italy) to retrieve a sample of Italian male
sexually active subjects with reported SARS-CoV-2 infection. A matching sample of
COVID-19-negative male sexually active subjects was also retrieved using propensity
score matching in a 3:1 ratio. The survey used different standardized psychometric
tools to measure effects of lockdown and social distancing on the intrapsychic, rela-
tional, and sexual health of Italian subjects.
Results: One hundred subjects were included in the analysis (25 COVID-positive; 75
COVID-negative). The prevalence of ED, measured with the Sexual Health Inventory
for Men, was significantly higher in the COVID+ group (28% vs. 9.33%; p = 0.027).
Logistic regression models confirmed a significant effect of COVID-19 on the devel-
opment of ED, independently of other variables affecting erectile function, such as
psychological status, age, and BMI [OR 5.66, 95% CI: 1.50–24.01]. Likewise, subjects
with ED were more likely to have COVID-19, once corrected for age and BMI [OR 5.27,
95% CI: 1.49–20.09].
Discussion and conclusion: On top of well-described pathophysiological mechanisms,
there is preliminary evidence in a real-life population of ED as a risk factor of develop-
ing COVID-19 and possibly occurring as a consequence of COVID-19. Universal vac-
cination against the COVID-19 and the personal protective equipment could possibly
have the added benefit of preventing sexual dysfunctions.

KEYWORDS
coronavirus, COVID-19, endothelial dysfunction, erectile dysfunction, SARS-CoV-2,
testosterone

© 2021 American Society of Andrology and European Academy of Andrology

Andrology. 2021;9:1053–1059.
Andrology. 2021;00:1–7.
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1 1| 
  |  I NTRO
I NTRO D UDCUTI
COTINO N 2  |hundred
Nine   M E TH
andOeighty-
D S five sexually active men were there-
fore identified in the Sex@COVID cohort, among which 25 (2.54%)
COVID-
Since19,
thethe coronavirus
first disease caused
case of coronavirus by the
disease severe
2019 acute respi-
(COVID-19), caused reported being tested
A systematic as positive
search for COVID-
of published 19. was conducted in the
studies
ratory syndrome
by severe coronavirus
acute 2 (SARS-
respiratory CoV-
syndrome 2), features 2several
coronavirus clin-
(SARS-CoV-2), PubMed and Ovid Embase databases for studies published from
icalwas
phenotypes,
reported ranging from
in Wuhan, mild to
China, severe
it has forms:
rapidly The “cytokine
spread and affected December 2019 to 18 August 2020 in accordance with PRISMA.38
storm”
more1,2
may lead
than to the development
21 million of microvascular
people worldwide 2020.1
thrombotic
as of 17 August 2.2 
All |  Measures
titles or abstracts of English-language studies were reviewed for
andSARS-CoV-2
inflammatoryuses
processes, which in turn promote
angiotensin-converting progression
enzyme to to
II (ACE2) eligibility. Citations and references of the retrieved studies were
possibly
enter lethal pulmonary
host cells, complications.
similar to Someemerged
SARS-CoV, which evidence
18has
years ago. 2 Anxiety
also usedand depressionsources.
as additional were, respectively,
There was no measured byon
limitation the GAD- size,
sample
18
suggested that induces
COVID-19 even “silent” asymptomatic forms ofmultiorgan
respiratory-predominant COVID-19 could
dysfunc- 7 (Generalized Anxiety
and case reports wereDisorder
included.Scale) and the
A full-text PHQ-
review 919performed
was (Patient by
3,4
have subclinical
tion, includingmicrovascular involvement
myocardial, renal, enteric andandhepatic
that long-term
dysfunction, Health Questionnaire),
2 independent two questionnaires
reviewers (Y.Y. and X.Y.) validated
on studiesfor clinical
that use, the
reported
3 5,6
cardiovascular sequelae
which coincides withcould be expected
the tissue in COVID-
expression 19 patients.
of ACE2. Meanwhile, which have already
detection been usedinto
of SARS-CoV-2 assess
the male psychological outcomes
reproductive tract, of
determined
20
Endothelial dysfunction
several studies have has been
shown considered
that as the potential
ACE2 is expressed trigger
in human testes COVID-
the 19.
impact For
of each test, scores
COVID-19 ≥10quality
on sperm are considered suggestive
and explored pathologi-
for (eg
the spermatogonia,
onset of more severe
Leydigforms, as well
cells and as the
Sertoli link
cells), 4,5between dif-
suggesting that of general anxiety
cal changes disorder
in the testes and depressive
of COVID-19 disorder,
patients. respectively.
Any disagreements
7
ferent comorbidities associated with COVID- 19 : Indeed,
the testes may be another organ affected by COVID-19. COVID- 19 Erectile function was measured by the IIEF-5, or Sexual
between reviewers were discussed with a third reviewer Health
(L.W.).
21,22
is by allNumerous
means an viruses
endothelial
havedisease, in which
been detected insystemic manifesta-
human semen. 6
Viruses Inventory for Men RoB
The Cochrane (SHIM),
2.0 toolawas
shortened, five-itemand
not applicable, version of the
the Newcastle-
23
tions of persist
may the disease can and
in semen potentially be due
last longer to tissue
in seminal ischemia
fluid result-
than in other body International Indexwas
Ottawa Scale of not
Erectile
usedFunction
due to the often
limitedused in of
scope thethe
clini-
cohort
ing fluids
from due
alterations in endothelial
to the immune thrombotic/fibrinolytic
privilege balance.8 of cal setting:
of the testes and the contribution Scores the
studies among 21 included
or belowstudies.
are considered suggestive of ED,
Additionally, endothelial cells express many of the co- factors used
7,8
the blood-testes barrier to resistance to therapeutic agents. Semen whereas scores 22– 25 are considered
The literature search in PubMednormal.
used the following search terms:
by the
maySARS- CoV-higher
also have 2 to invade host
loads of cells.9such as Zika virus, than blood.9,10
viruses, (“2019 new coronavirus” [All Fields] OR “2019 ncov” [All Fields] OR
Erectile dysfunction
Therefore, (ED) act
the testes may hasasbeen often considered
a reservoir a hallmark
of virus, which may cause “severe acute respiratory syndrome coronavirus 2” [All Fields] OR
of endothelial dysfunction,10,11
and as such, a potential association
imprecise evaluation of viral clearance in patients. Viruses, including 2.3 
“sars Statistical
| cov analysis
2” [All Fields] OR “coronavirus disease 2019” [All Fields]
12
between ED and
Zika virus, COVID-
Ebola virus, 19 has also been and
cytomegalovirus postulated.
human immunodeficiency OR “covid19” [All Fields] OR “covid 19” [All Fields]) AND (“semen”
Another
virus (HIV),interesting
have beentake on the
isolated fromassociation
semen and between ED and
can be sexually trans- Statistical analysis
[All Fields] was performed
OR “sperm” with
[All Fields] OR the statistical
“testis” software
[All Fields] R
OR “testes”
COVID- 19
mitted. comes
6,11,12 from the shared risk factors for the two condi-
Furthermore, some viruses (eg HIV, Zika virus, herpes (version 3.6.2); statistical significance was set at p < 0.05. Propensity
[All Fields] OR “testicular” [All Fields] OR “epididymis” [All Fields] OR
tions. Indeed,
simplex severity
virus (HSV)and
andprevalence of both ED and
human papillomavirus) canCOVID-
adhere19toare
or be score matchingfluid”
“spermatic was used in orderOR
[All Fields] to “seminal
retrieve two
fluid”matching samples,
[All Fields] OR “pros-
higher among men suffering
internalized by spermatozoa,from
7,13 hypertension, obesity, diabetes,
which may pose a risk for embryonic based on age, body mass index (BMI), and GAD- 7 and PHQ-
tatic secretion” [All Fields] OR “prostatic fluid” [All Fields]9 scores,
OR “male
13-16
andinfection
history of
andcardiovascular
cause adverse disease.
reproductiveBroadly speaking, ED is
outcomes. using a 1:3 ratio to
reproductive improve
tract” reliability
[All Fields] ORof“male
the results.
genital Assessment of
tract” [All Fields]).
often considered
On the other a clinical marker
hand, many of a “dysfunctional”
viruses, such as mumpsphenotype,
virus, HIV and normality
Searcheswasin performed
Ovid Embase using
usedthe
theShapiro- Wilk
following test (‘2019
terms: of normal-
ncov’ OR
which
HSV,often
7,14 features cardiovascular events at an early age. This
have been found to impair semen quality, and they may di- ity. Wilcoxon
‘sars cov 2’ OR ‘covid-19’ OR covid19) AND (semen ORFisher's
rank sum test with continuity correction and sperm OR
would possibly
rectly suggest
interact with that subjects with
spermatozoa ED, due
or affect to the underlying
spermatogenesis by in- exact testOR
testis (one- tailed)
testes ORwere used toOR
testicular assess differences
epididymis in the numeri-
OR ‘spermatic fluid’ OR
conditions whichinflammation.
ducing local impair erectile response,
15-17
Previouscould alsofound
studies be more
thatsus-
SARS, cal and categorical
‘seminal fluid’ ORvariables between
‘prostatic study
secretion’ groups. Chi-
OR ‘prostatic squared
fluid’ OR ‘male
ceptible to contracting COVID- 19.
1 of the 3 epidemic coronaviruses to emerge in the past 20 years goodness- of-fit test was used to measure differences
reproductive tract’ OR ‘male genital tract’). in the preva-
The that
and present study
shows is, toclinical
similar our knowledge, the first
presentations one investigat-
to COVID-19, 18
could lence of ED between study groups. Logistic regression models were
ing cause
the prevalence
orchitis 19of
andEDfocal
and testicular
the possible association
atrophy. 20 betweenthe
Considering EDtens fitted to assess to which extent age, GAD-7 and PHQ-9 scores, BMI,
andofCOVID- 19of
millions from real-lifecases
COVID-19 data in a large
and that survey.
men are more vulnerable to and 3 
history
|   of
R ECOVID-
S U LT19S affected
A N D erectile
DISCU function
S S I O and
N to measure
COVID-19 than women, 21-23
it is imperative to determine the effect the effect of age, BMI, and ED on the susceptibility to COVID-19.

of COVID-19 on male reproduction. 24
2  |  Several
M ATE R I A Lhave
studies S A been
ND M E TH O DS
performed on this topic. However,
the results are controversial. For example, some researchers have 2.4  |  Power
2.1  |  Subjects
reported that SARS-CoV-2 was not detected in the male reproduc-
tive tract, 25-34 while others reported that SARS-CoV-2 RNA was
In order
foundtoinretrieve
the semenan adequate
or testes sample for thepatients.
of COVID-19 present35,36
study, we are
There
17
reviewed data from the Sex@COVID study, a previous research
also unknown factors regarding COVID-19 and male reproduction.
project by our group. The Sex@COVID study was an anonymous
Orchitis and broad destruction of the testes were found in deceased
web-based questionnaire investigating the psychological, relational,
COVID-19 patients,35,37 while the pathological characteristics in
and sexual health of Italian subjects between April 7 and May 4,
survivors remain unknown. In this review, we summarize the current
2020.
research focusing on the effects of COVID-19 on male reproduc-
Overall, 6821 subjects aged 18 years or older (females, 4177;
tion from the following 3 aspects: detection of SARS-CoV-2 in the
males, 2644; mean age 32.83 ± 11.24 years) living in Italy, stratified
male reproductive tract, determination of the impact of COVID-19
according to marital status and sexual activity during lockdown,
on sperm quality and exploration of pathological changes in the tes-
participated in the Sex@COVID study. All subjects provided in-
tes of COVID-19 patients. We further discuss the discrepancies and
formed consent to the study, which has been approved by our local
summarize the unknown topics, which we believe will be helpful for
Ethical Committee.
future research.
After reviewing the studies retrieved from the database, citations
and references were added based on a review of the title or abstract
(Figure analysis
1). Fourteen studies were eligible and were included in this
study, with 12 studies detecting SARS-CoV-2 in the male reproduc-
Sample
tive size was
tract, 3 calculated
determiningbased
the on a 28%ofprevalence
impact COVID-19ofon EDsperm
amongqual-
the ity
COVID+group, using a 0.8 effect size (accounting for a large
and 3 exploring pathological changes in the testes of COVID-19ef-
fect size), with 1:3 ratio, α = 0.05, and power 0.95. According to these
patients.
calculations, a total sample size of 87 (22 COVID+, 65 COVID−) was
needed. By including 25 COVID+ and 75 COVID− subjects, the post-
hoc analysis yielded a 0.97 statistical power.
3.1  |  Detection of COVID-19 in the male
reproductive tract
3 Twelve
|  R Estudies
S U LTinvestigated
S the presence of SARS-CoV-2 in the male
reproductive tract (eg semen, prostatic secretion or testicular tis-
According to the suggested propensity score matching approach
sue) and are shown in Table 1. Most studies were cross-sectional
detailed above, 100 subjects from the 985 sexually active men
in design and included mainly Chinese subjects. In brief, ten of 12
belonging to the Sex@COVID cohort were retrieved: 25 subjects
studies reported that none of the participants had SARS-CoV-2 RNA
SANSONE et
SANSONE Al. .
Etal |
2          |
 3
1055

reported having contracted COVID-19 (COVID+), and a matching 1 

on|   I NTRO
erectile D U Cmight
function TI O N
be an additional cause of worry in 2   |  M
sample (based on age, BMI, and GAD-7 and PHQ-9 scores) of 75 COVID-19 patients. In the present study, to our best knowledge,
subjects was recruited among those having no history of SARS- we investigated
Since the first casefor the first timedisease
of coronavirus the possible association between
2019 (COVID-19), caused A system
CoV-2 infection prior to filling the Sex@COVID survey (COVID-). byerectile function
severe acute and COVID-
respiratory 19 in a coronavirus
syndrome real-life setting. Results of our
2 (SARS-CoV-2), PubMed
Descriptive data of the study population are reported in Table 1. study
was agreeinwith
reported the pathophysiological
Wuhan, mechanisms
China, it has rapidly spread andlinking ED,
affected Decembe
According to propensity score matching, no statistically significant endothelial
more than 21dysfunction, andworldwide
million people COVID-19. as
By of
performing 2020.1
propensity
17 August All titles
difference was found for age, GAD-7 and PHQ-9 scores, and BMI score matching,
SARS-CoV-2 uses we removed the possibleenzyme
angiotensin-converting bias resulting from to
II (ACE2) age eligibility
between the two groups. The prevalence of ED was higher in the andhost
enter BMI,cells,
factors which
similar contributewhich
to SARS-CoV, to both increased
emerged ago. 2
prevalence
18 years used as a
COVID+group (7/25, 28%) than in the COVID- group (7/75, 9.33%; of ED13,14induces
COVID-19 and increased susceptibility to COVID-
respiratory-predominant 19.15,16 Therefore,
multiorgan dysfunc- and case
p-value 0.0274) (Figure 1). ourincluding
tion, results are highly suggestive
myocardial, of the and
renal, enteric role hepatic
of the infection in the
dysfunction, 2 indepe
Logistic regression models confirmed the association of development 3
which coincidesof the the
with sexual dysfunction
tissue and
expression ofofACE2.
the possible clinical
Meanwhile, detection
COVID-19 with ED of COVID-19 on the development of ED (Table 2): relevance
several of have
studies COVID- 19 as
shown an ACE2
that additional risk factor
is expressed for thetestes
in human devel- the impa
While age, BMI, and psychological health scores failed to reach sta- opment of ED. Additionally, considering the bidirectional
4,5 interac-
(eg spermatogonia, Leydig cells and Sertoli cells), suggesting that cal chang
tistical significance, history of COVID-19 was highly significant, re- thetion between
testes may besexual activity
another and psychological
organ affected well-being,17 the
by COVID-19. between
sulting in a 5.66 odds ratio [95% confidence interval: 1.50–24.01] of removal of the
Numerous possible
viruses influence
have been of anxiety
detected andsemen.
in human depression
6 con-
Viruses The Coch
having ED. mayfirmed that
persist the increased
in semen prevalence
and last longer of ED
in seminal here
fluid found
than is not
in other only
body Ottawa S
Since ED could be a valid clinical marker of several underlying fluids due to the immune privilege of the testes and the contribution also
a consequence of the psychological burden of lockdown, but of studies a
and unaccounted conditions, such as diabetes and hypertension, we theprominently
blood-testesdue to other,
barrier bona fide
to resistance to organic factors,
therapeutic among
agents. 7,8 which
Semen The li
also measured in the same sample the likelihood of having a self- mayendothelial dysfunction
also have higher loads ofisviruses,
the most
such likely
as Zikaculprit. On blood.
virus, than the other
9,10
(“2019 ne
reported history of COVID-19 following a diagnosis of ED. Logistic hand, there
Therefore, the istestes
another
mayplausible explanation:
act as a reservoir ED iswhich
of virus, a well-may
recognized
cause “severe a
11
regression models adjusted for age and BMI (Table 3) showed a sig- surrogate marker of systemic health, and therefore, ED patients
imprecise evaluation of viral clearance in patients. Viruses, including “sars cov
nificant association between ED and COVID-19, with a 5.27 odds could
Zika already
virus, carry cytomegalovirus
Ebola virus, several underlying
andand unexplored
human risk factors,
immunodeficiency OR “covi
ratio [95% CI: 1.49–20.09]. such
virus as dyslipidemia,
(HIV), diabetes,
have been isolated fromand hypertension,
semen which could
and can be sexually trans-in- [All Field
crease
mitted. the Furthermore,
6,11,12 likelihood of contracting
some virusesCOVID- 19.Zika
(eg HIV, Hence, weherpes
virus, also in- [All Field
vestigated whether subjects with ED, owing to the worse
simplex virus (HSV) and human papillomavirus) can adhere to or besystemic “spermat
4  |   D I S C U S S I O N health,11 could
internalized possibly be
by spermatozoa, 7,13more at risk of developing COVID-19.
which may pose a risk for embryonic tatic secr
Based and
infection on our preliminary
cause results, EDoutcomes.
adverse reproductive and COVID-19 seem to be reproduc
The large majority of the studies investigating the effects of strongly associated,
On the other hand, with
manyCOVID-
viruses,19 increasing
such thevirus,
as mumps chances
HIVof
andde- Searches
COVID-19 on male sexual and reproductive health have focused veloping
HSV,7,14
have been found to impair semen quality, and they may di-to
ED and ED being a marker of increased susceptibility ‘sars cov
on fertility and its preservation, 24-30 and to the present date, there infection.
rectly While
interact withmore adequately
spermatozoa or tailored studies are needed,
affect spermatogenesis we
by in- testis OR
seems to be no definite evidence of the presence of SARS- CoV-2 in ducing local inflammation.15-17 Previous studies found that SARS, ‘seminal
seminal fluid31,32 ; however, there is reason to suspect that sexual 1 of the 3 epidemic coronaviruses to emerge in the past 20 years reproduc
quality of life and function might also be impaired as a consequence and that shows similar clinical presentations to COVID-19,18 could
of COVID-19.12,33,34 While of course this is of relative importance cause orchitis 19 and focal testicular atrophy. 20 Considering the tens
to patients in intensive care units, the possible long-term effects of millions of COVID-19 cases and that men are more vulnerable to 3   |  R
COVID-19 than women, 21-23 it is imperative to determine the effect
of COVID-19 on male reproduction. 24 After rev
TA B L E 1  Characteristics of the study population
Several studies have been performed on this topic. However, and refer
COVID+ COVID- the results are controversial. For example, some researchers have (Figure 1
(n = 25) (n = 75) p-value reported that SARS-CoV-2 was not detected in the male reproduc- study, wi
Age (years) 39.00 [29.00, 45.00] 42.00 [32.50, 49.00] 0.142   a tive tract, 25-34 while others reported that SARS-CoV-2 RNA was tive tract
2
BMI (kg/m ) 22.65 [20.83, 23.74] 22.74 [20.98, 24.53] 0.266   a found in the semen or testes of COVID-19 patients.35,36 There are ity and 3

GAD−7 score 4.00 [2.00, 6.00] 4.00 [2.00, 5.00] 0.741a  also unknown factors regarding COVID-19 and male reproduction. patients.
a Orchitis and broad destruction of the testes were found in deceased
PHQ−9 score 5.00 [3.00, 6.00] 4.00 [2.00, 5.00] 0.873  
COVID-19 patients,35,37 while the pathological characteristics in
Erectile 7 (28%) 7 (9.33%) 0.027b 
dysfunction survivors remain unknown. In this review, we summarize the current 3.1  | 
research focusing on the effects of COVID-19 on male reproduc- reprodu
Statistically significant values highlighted in bold.
tion from the following 3 aspects: detection of SARS-CoV-2 in the
All data expressed as median [interquartile range] except prevalence of
erectile dysfunction, expressed as n (%). male reproductive tract, determination of the impact of COVID-19 Twelve st
Abbreviations: BMI, body mass index; GAD-7, Generalized Anxiety on sperm quality and exploration of pathological changes in the tes- reproduc
Disorder Scale;HQ-9, Patient Health Questionnaire. tes of COVID-19 patients. We further discuss the discrepancies and sue) and
a
Wilcoxon rank sum test with continuity correction; bFisher's exact test F I G U R Ethe
summarize 1  Prevalence of erectile
unknown topics, which dysfunction in the
we believe will be COVID+
helpful for in design
(one-tailed). and COVID− groups
future research. studies re
4  | |
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1056 SANSONEYAO
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TA B L E 2  Results of logistic regression

1   |  I NTRO D U C TI O N 2  |ratio
Odds   M E TH O Dmodels
S for erectile dysfunction (ED)
Estimate Std. error p-value [95% CI]
according to age, body mass index (BMI),
Since the first case of coronavirus
Intercept −9.607 disease 2019 (COVID-19),
3.216 caused
0.003 A systematic search psychological
0.00 of publishedhealth,
studiesand
was conducted
self- referred in the
by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [0.00–
PubMed0.02]and Ovid Embase
history of COVID-19.
databases forPHQ- 9: Patient
studies published from
Age
was(years) 0.062 it has rapidly
reported in Wuhan, China, 0.027
spread and0.023
affected 1.06 [1.01–1.13]
December Health
2019 to 18 Questionnaire
August and GAD-
2020 in accordance 7: PRISMA.38
with
Generalized Anxiety Disorder Scale
BMI 0.143
more than 21 million people 0.106
worldwide as of 17 August 2020.1
0.178 1.15 [0.93–or
All titles 1.43]
abstracts of English-language studies were reviewed for
SARS-CoV-2
GAD−7 score uses angiotensin-converting
0.114 enzyme II (ACE2)
0.193 0.556 to eligibility.
1.12 Citations and references of the retrieved studies were
[0.77–1.66]
2
enter score
PHQ−9 host cells, similar to SARS-CoV,
0.148 which 0.143
emerged 18 years
0.301ago. used[0.88–
1.16 as additional
1.55] sources. There was no limitation on sample size,
COVID-19
Previous induces respiratory-predominant
COVID−19 1.734 multiorgan 0.013
0.694 dysfunc- and case reports were included. A full-text review was performed by
5.66
tion, including myocardial, renal, enteric and hepatic dysfunction, [1.50–24.01]
2 independent reviewers (Y.Y. and X.Y.) on studies that reported the
which coincides with the tissue expression of ACE2.3 Meanwhile, detection of SARS-CoV-2 in the male reproductive tract, determined
several studies have shown that ACE2 is expressed in human testes the impact of COVID-19 on sperm quality and explored pathologi-
5,53
TA (eg
B L Espermatogonia,
3  Results of logistic regression models for COVID
4,5
Leydig cells and Sertoli cells), suggesting that and involving
cal changesthe same
in the cytokines
testes of COVID-19 could be promoted
patients. by the
Any disagreements
according to age, body mass index (BMI), and erectile
the testes may be another organ affected by COVID-19. dysfunction hypogonadal state encountered in affected patients.
between reviewers were discussed with a third reviewer The immu-(L.W.).
(ED)
Numerous viruses have been detected in human semen. Viruses nothrombosis
6
The Cochranecould
RoBpotentially affect
2.0 tool was notthe penile vessels,
applicable, and the trigger-
Newcastle-
longer in seminal fluid than in other body ing endothelial
may persist in semen and lastStd. Ottawa Scale dysfunction—
was not usedtherefore
due to impairing
the limitedvascular function
scope of the cohort
fluids due to the Estimate error ofp-
immune privilege value
the testesOdds ratio
and the [95% CI] of and studies
contribution promoting progression
among to studies.
the included more severe forms of sexual dys-
54,55
the blood-testes barrier
Intercept 1.910 to resistance
2.194 0.384to therapeutic
6.75 [0.11–
7,8
661.99]Semen
agents. function. Other cardiovascular
The literature search in PubMed complications of COVID-
used the following search19,
terms:
56,57
may
Age also have higher
(years) loads of0.021
−0.027 viruses,0.197
such as Zika
0.97virus,
[0.93–than
1.01]blood. such(“2019
9,10 as cardiomyopathy
new coronavirus”and[All
myocarditis,
Fields] OR “2019could
ncov”also
[All be in- OR
Fields]
Therefore, the testes may act as a reservoir of virus, which may cause volved in the
“severe pathogenesis
acute respiratoryofsyndrome
ED even after the end2”
coronavirus of[All
the Fields]
acute OR
BMI −0.096 0.089 0.281 0.91 [0.76–1.07]
5,6
imprecise evaluation of viral clearance in patients. Viruses, including phase,
Presence of ED 1.662 0.652 0.011 5.27 [1.49–20.09]
potentially
“sars becoming
cov 2” [All long-
Fields] OR term cardiovascular
“coronavirus sequelae.
disease 2019” [All Fields]
Zika virus, Ebola virus, cytomegalovirus and human immunodeficiency Other ORpotential
“covid19”factors couldOR
[All Fields] contribute to impaired
“covid 19” erectile
[All Fields]) ANDfunc-
(“semen”
58,59
virus (HIV), have been isolated from semen and can be sexually trans- tion[All
in COVID- 19 patients,
Fields] OR such
“sperm” [All as pulmonary
Fields] fibrosis
OR “testis” [All Fields] causing
OR “testes”
60,61
believe that
mitted. our Furthermore,
6,11,12 study highlights
some theviruses
possible
(egrelevance
HIV, Zikafor sexual
virus, herpes hypoxia in theOR
[All Fields] penile vascular
“testicular” [Allbed,
Fields] ORor “epididymis”
anosmia and[All ageusia,
Fields] OR
62,63
medicine and andrology of COVID- 19 spectrum of disease and
simplex virus (HSV) and human papillomavirus) can adhere to or be its both
“spermatic fluid” [All Fields] OR “seminal fluid” [All Fields] ORef-
manifestations of COVID- 19 with possible negative “pros-
64- 67
short and long-by
internalized term health consequences.
spermatozoa, 7,13
which may pose a risk for embryonic fects on secretion”
tatic sexual health.
[All Fields]While these factors
OR “prostatic could
fluid” [All possibly
Fields] OR “male
There is and
infection a solid pathogenetic
cause background
adverse reproductive for the mechanisms
outcomes. havereproductive
a minor influence when
tract” [All considered
Fields] OR “maleindividually, the[All
genital tract” likely
Fields]).
12
through which COVID- 19 could affect erectile function. Many
On the other hand, many viruses, such as mumps virus, HIV and presence of most, if not all, of them at the same time could
Searches in Ovid Embase used the following terms: (‘2019 ncov’ OR easily
machineries through
HSV,7,14 have been which SARS-
found to CoV-
impair 2 invades
semen quality,the
andhost
theycells
may di- allow thecov
‘sars progression from a subclinical
2’ OR ‘covid-19’ OR covid19) to AND
an overt formOR
(semen of sexual
sperm OR
68,69
have been identified: The virus uses angiotensin- converting en-
rectly interact with spermatozoa or affect spermatogenesis by in- dysfunction. Considering the subclinical, yet non- negligible,
testis OR testes OR testicular OR epididymis OR ‘spermatic fluid’ OR
4
zyme 2 (ACE2)
ducing local as an entry point
inflammation. 15-17to the cells, and primes the spike
Previous studies found that SARS, cardiopulmonary
‘seminal fluid’ damage reported
OR ‘prostatic in asymptomatic
secretion’ subjects,
OR ‘prostatic fluid’ ORwe‘male
protein, which facilitates viral entry into target cells, by employing
1 of the 3 epidemic coronaviruses to emerge in the past 20 years speculate that the same progression from subclinical
reproductive tract’ OR ‘male genital tract’). to an overt
35
theand
transmembrane protease,
that shows similar serine
clinical 2 TMPRSS2.
presentations The SARS-
to COVID-19, 18
could sexual dysfunction could also occur in subjects with “silent” forms
CoV- 2 therefore
cause shows
orchitis 19 sometesticular
and focal similarities with 20another
atrophy. coronavi-
Considering the tens of COVID-19 in the presence of additional risk factors—being the
36,37
rus,of millions
namely SARS- CoV,cases
of COVID-19 the and
virusthat
strain
menresponsible for the to proverbial
are more vulnerable 3  |  straw
R E Sthat
U LTbreaks
S AN the
Dcamel's
D I S Cbreak.
USSION
SARS outbreak
COVID-19 occurring
than women,in 2003–
21-23 2004. 37-39 to
it is imperative Since adult Leydig
determine the effect Based on the presented evidence and on similarities to previ-
cells express ACE- 2, testicular involvement
of COVID-19 on male reproduction. 24 due to COVID- 19 has ous coronavirus
After diseases,
reviewing ED could
the studies therefore
retrieved frombethe
both a short-term
database, citations
40 41
been hypothesized and confirmed in autopsy reports.
Several studies have been performed on this topic. However, Also, at and and references were added based on a review of the titleassocia-
a long-term complication of COVID- 19. The potential or abstract
least
theone caseare
results of acute orchitis For
controversial. following
example,SARS- CoV-
some 2 infectionhave tion(Figure
researchers between 1). ED and COVID-
Fourteen 19were
studies might increase
eligible andawareness of the
were included in this
42
hasreported
been reported. The testicular injury reported in these studies
that SARS-CoV-2 was not detected in the male reproduc- importance of personal protective equipment, such as masks, and
study, with 12 studies detecting SARS-CoV-2 in the male reproduc-
could
tivealso be25-34
tract, a consequence
while othersof reported
alterationsthat
in the coagulative
SARS-CoV-2 sta-was social
RNA tivedistancing in a harm reduction
tract, 3 determining the impactperspective foronlong-
of COVID-19 termqual-
sperm
43 70
tus,found
resulting in development
in the of ischemia
semen or testes at a microvascular
of COVID-19 patients.35,36level.
There are consequences. The use
ity and 3 exploring of masks changes
pathological as devices for testes
in the the prevention
of COVID-19
Independently of the etiology, testicular damage can possibly lead of sexual dysfunctions is perhaps a bit stretched, but at present
also unknown factors regarding COVID-19 and male reproduction. patients.
to the development of a form of hypergonadotropic hypogonad- we believe that this could also possibly be an additional strategy to
Orchitis and broad destruction of the testes were found in deceased
ism 44- 48 : As testosterone modulates endothelial function,49 the promote the use of personal protective equipment—as people have
COVID-19 patients,35,37 while the pathological characteristics in
possible effects of COVID-19 on erection could also be indirectly already posted on Twitter, using the hashtag “#MaskUpToKeepItUp.”
survivors remain unknown. In this review, we summarize the current 3.1  |  Detection of COVID-19 in the male
due to impaired testosterone secretion from the affected testis, Additionally, subjects with a sudden onset or worsening of ED might
research focusing on the effects of COVID-19 on male reproduc- reproductive tract
besides the known direct effects of testosterone in male sexual also consider precautionary quarantine or nasopharyngeal swab, as
tion from the following 3 aspects: detection of SARS-CoV-2 in the
response. 50 Additionally, as higher testosterone levels are also as- COVID-19 might act as a potential initiating trigger for the onset of
male reproductive tract, determination of the impact of COVID-19 Twelve studies investigated the presence of SARS-CoV-2 in the male
sociated with lower levels of pro-inflammatory cytokines such as erectile impairment, or an aggravating factor for its progression to
on sperm quality and exploration of pathological changes in the tes- reproductive tract (eg semen, prostatic secretion or testicular tis-
tumor necrosis factor alpha (TNF- α), interleukins (IL- 6 and IL-1β), more severe forms.
tes of COVID-19 patients. We further discuss the discrepancies and sue) and are shown in Table 1. Most studies were cross-sectional
and higher levels of anti-inflammatory cytokines (such as IL-10), 51 Likewise, subjects with ED should consider their erectile im-
summarize the unknown topics, which we believe will be helpful for in design and included mainly Chinese subjects. In brief, ten of 12
the “immunothrombotic” mechanism described for COVID-1952 pairment as a sign of possible underlying conditions which could
future research. studies reported that none of the participants had SARS-CoV-2 RNA
SANSONE et
SANSONE Al. .
Etal |
2           5
1057|

increase the likelihood of suffering from COVID-19. Therefore, the 1   EIRNTRO

R E| F E N C E SD U C TI O N 2   |  M
importance of investigating the possible causes of ED becomes of 1. Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP. The trinity of
paramount importance in times like these: Identifying and treat- Since the COVID- 19: immunity,
first case of coronavirus inflammation
disease 2019 and (COVID-19),
intervention. caused
Nat Rev A system
Immunol. 2020;20(6):363-374. https://doi.org/10.1038/s4157
ing potential comorbidities would have potentially beneficial ef- by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), PubMed
7- 020- 0311-8
fects on erectile function, while at the same time reducing the was2.reported
Jose RJ,in Wuhan,
Manuel China,19
A. COVID- it cytokine
has rapidly
storm: spread and affected
the interplay between Decembe
risk of contracting SARS- CoV-2 or developing more severe forms more than 21 million
inflammation andpeople worldwide
coagulation. Lancetas of 17
Respir Med.August 2020.1
2020;8(6):e46- All titles
of COVID-19. SARS-CoV-2e47. https://doi.org/10.1038/s4157
uses angiotensin-converting 7- 020- 0311-8 II (ACE2) to
enzyme eligibility
3. Oran DP, Topol EJ. Prevalence of asymptomatic SARS-CoV-2 2in-
The present study has several limitations, including its retro- enter host cells, similar to SARS-CoV, which emerged 18 years ago. used as a
fection: a narrative review. Ann Intern Med. 2020;173(5):362-367.
spective nature, the recall bias associated with the use of online COVID-19 induces respiratory-predominant
https://doi.org/10.7326/M20- 3012 multiorgan dysfunc- and case
questionnaires, and the inclusion of diagnosis of COVID-19 based on tion,4. including
Long QX, myocardial,
Tang XJ, renal,Shi QL, enteric
et al.and hepatic
Clinical anddysfunction,
immunologi- 2 indepe
the response to the survey, rather than on nasopharyngeal swabs. cal assessment
which coincides with the of tissue
asymptomatic
expression SARS- of CoV-
ACE2. 2 3infections.
Meanwhile, Nat detection
Med. 2020;26(8):1200-1204. https://doi.org/10.1038/s4159
Additionally, as the survey did not investigate the potential comor- several studies have shown that ACE2 is expressed in human testes the impa
1- 020- 0965-6
bidities (such as diabetes, endocrine disorders, and hypertension (eg 5.
spermatogonia, 4,5
Liu PP, Blet A,Leydig
Smyth D, cells
Li H.andTheSertoli
science cells),
underlyingsuggesting
COVID-19: that im- cal chang
13,50,54,71-73 54,71
), treatments (such as anti-depressants ), and life- the testes may be
plications foranother organ affected
the cardiovascular system. byCirculation.
COVID-19. 2020;142(1):68- between
14,54,74 78. https://doi.org/10.1161/CIRCU LATIO NAHA.120.047549
styles (such as smoking ) affecting sexual health, these find- Numerous viruses have been detected in human semen.6 Viruses The Coch
ings only provide preliminary evidence of the association between 6. Vittori A, Lerman J, Cascella M, et al. COVID-19 pandemic acute re-
may persist in semen and last longer in seminal fluid than in other body Ottawa S
spiratory distress syndrome survivors: pain after the storm? Anesth
COVID-19 and erectile dysfunction. However, at the time of the first fluids due to the immune privilege
Analg. 2020;131(1):117- 119.of https://doi.org/10.1213/ANE.00000
the testes and the contribution of studies a
Italian lockdown here explored, swabs were rarely available, and an the blood-testes
00000 004914 barrier to resistance to therapeutic agents.7,8 Semen The li
online survey was the most reliable way to obtain information on may7.alsoBernard I, Limonta
have higher loads D, Mahal LK,
of viruses, Hobman
such as ZikaTC. Endothelium
virus, than blood.infec-
9,10
(“2019 ne
a large cohort of patients without breaking restrictions. While our tion and dysregulation by SARS-CoV-2: evidence and caveats in
Therefore, the testes may act as a reservoir of virus, which may cause “severe a
COVID-19. Viruses. 2021;13(1):29. https://doi.org/10.3390/v1301
study could not include such data, based on the study design, more imprecise evaluation of viral clearance in patients. Viruses, including “sars cov
0029
studies adequately tailored to investigate the endocrine function, Zika8.virus,
LibbyEbola virus, cytomegalovirus
P, Luscher T. COVID-19 is, in and
thehuman
end, animmunodeficiency
endothelial disease. OR “covi
most importantly testosterone, and penile vascular dynamics in pa- Eur have
virus (HIV), Heartbeen J. 2020;41(32):3038-
isolated from semen 3044.
and https://doi.org/10.1093/
can be sexually trans- [All Field
tients with a history of COVID-19 are needed to provide definite eurheartj/ehaa623
mitted.6,11,12 Furthermore, some viruses (eg HIV, Zika virus, herpes [All Field
9. Pons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the
evidence; however, at present our findings, no matter how limited, simplexcornerstone
virus (HSV)ofand human papillomavirus)
organ dysfunction in severecan SARS-adhere
CoV-2toinfection.
or be “spermat
are highly suggestive of a potential long-term risk for male sexual internalized by spermatozoa,
Crit Care. 2020;24(1): 353.
7,13
which may pose a risk for embryonic
https://doi.org/10.1186/s1305 4- 020- tatic secr
function following COVID-19. infection 03062 -7
and cause adverse reproductive outcomes. reproduc
10. Guay AT. ED2: erectile dysfunction = endothelial dysfunction.
On the other hand, many viruses, such as mumps virus, HIV and Searches
Endocrinol Metab Clin North Am. 2007;36(2):453- 463. https://doi.
AC K N OW L E D G M E N T S HSV,7,14org/10.1016/j.ecl.2007.03.007
have been found to impair semen quality, and they may di- ‘sars cov
None. rectly
11. interact
Jannini EA. with SMspermatozoa
= SM: The interfaceor affect of spermatogenesis
systems medicine and by in-
sex- testis OR
ducing ual localmedicine for facing
inflammation. 15-17non-communicable diseases in a gender-
Previous studies found that SARS, ‘seminal
C O N FL I C T S O F I N T E R E S T dependent manner. Sex Med Rev. 2017;5(3):349-364. https://doi.
1 of the 3 epidemic coronaviruses to emerge in the past 20 years reproduc
org/10.1016/j.sxmr.2017.04.002
The authors declare no competing interests for the present study. and 18
12.that shows A,
Sansone similar clinical
Mollaioli presentations
D, Ciocca G, et al.to COVID-19,
Addressing malecould
sexual
19 20
cause orchitis and focalhealth
and reproductive testicular
in the atrophy.
wake of Considering the tens J
COVID-19 outbreak.
AU T H O R ' S C O N T R I B U T I O N S Endocrinol
of millions 2021;44(2):223-
Investig.cases
of COVID-19 and that men 231.are https://doi.org/10.1007/
more vulnerable to 3   |  R
Conceptualization, AS, DM and EAJ; data curation, AS and DM; for- s40618- 020- 01350 -1
21-23
COVID-19 than women, it is imperative to determine the effect
mal analysis, AS and DM; investigation, AS, DM, GC, EL, EC; meth- 13. Romanelli F, Sansone A, Lenzi A. 24
Erectile dysfunction in aging male.
of COVID-19 on male
Acta Biomed. reproduction.
2010;81(Suppl 1):89-94. After rev
odology, AS and DM.; project administration and supervision, EAJ; Several studies have G, been performed
14. Mollaioli D, Ciocca Limoncin E, et al.onLifestyles
this topic.andHowever,
sexuality in and refer
validation, EAJ; visualization, AS; writing—original draft, AS and DM; men and women: the gender perspective
the results are controversial. For example, some researchers have in sexual medicine. Reprod (Figure 1
writing—review and editing, GC, EL, EC, GB and EAJ. We attest that Biol Endocrinol. 2020;18(1): 10. https://doi.org/10.1186/s1295
reported that SARS-CoV-2 was not detected in the male reproduc- study, wi
all authors contributed significantly to the creation of this manu- 8- 019-
25-34
0557-9
tive
15.tract,
Mahase E. while
Covid- others
19: Why reported
are age that SARS-CoV-2
and obesity RNAforwas
risk factors seri- tive tract
script. We confirm that the order of authors listed in the manuscript found in the semen or testes of COVID-19 patients. 35,36
There are ity and 3
ous disease? BMJ. 2020;371: m4130. https://doi.org/10.1136/bmj.
has been approved by all named authors. All authors have read and m4130 factors regarding COVID-19 and male reproduction.
also unknown patients.
agreed to the published version of the manuscript. 16. Caci G, Albini A, Malerba M, Noonan DM, Pochetti P, Polosa
Orchitis and broad destruction of the testes were found in deceased
R. COVID-1935,37 and obesity: dangerous liaisons. J Clin Med.
COVID-19 2020;9(8):2511. while the pathological characteristics
patients, https://doi.org/10.3390/jcm90 82511 in
ORCID
survivors remainD,unknown.
17. Mollaioli Sansone A, In Ciocca
this review,
G, et we summarize
al. Benefits the current
of sexual activity 3.1  | 
Andrea Sansone https://orcid.org/0000-0002-1210-2843
research onfocusing
psychological,on therelational,
effectsand of sexual
COVID-19 healthon during
malethe COVID-19
reproduc- reprodu
Daniele Mollaioli https://orcid.org/0000-0001-5947-3310 breakout. J Sex Med. 2021;18(1):35- 49. https://doi.org/10.1016/j.
tion from the following 3 aspects: detection of SARS-CoV-2 in the
Giacomo Ciocca https://orcid.org/0000-0002-4256-1776 jsxm.2020.10.008
male reproductive tract, determination of the impact of COVID-19
18. Lowe B, Decker O, Muller S, et al. Validation and standardization
Twelve st
Elena Colonnello https://orcid.org/0000-0002-0081-7163
on sperm of quality and exploration
the Generalized Anxietyof Disorder
pathological changes
Screener in the
(GAD- 7) intes-the reproduc
Giancarlo Balercia https://orcid.org/0000-0003-1286-1521 general population. Medfurther 2008;46(3):266-
Care. discuss 274. https://doi.
tes of COVID-19 patients. We the discrepancies and sue) and
Emmanuele A. Jannini https://orcid.org/0000-0002-5874-039X org/10.1097/MLR.0b013e318160d093
summarize the unknown topics, which we believe will be helpful for in design
future research. studies re
1058
6  | |
2     
    SANSONEYAO
SANSONE al..et Al .
etAl
Et

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Testicular search
pain as anin unusual
PubMedpresentation
used the followingof COVID-search
19: terms:
a
9,10
may also have
syndrome- higher loads
coronavirus 2 inofsemen
viruses, ofsuch
males asrecovering
Zika virus, from
than blood.
coro- (“2019 new coronavirus”
brief review of SARS-CoV- [All Fields]
2 and OR “2019
the testis. Reprodncov” [All Online.
Biomed Fields] OR
navirus disease
Therefore, 2019.may
the testes Fertil
actSteril. 2020;113(6):1135-
as a reservoir of virus, 1139.
whichhttps://
may cause 2020;41(5):903-
“severe 906. https://doi.org/10.1016/j.rbmo.2020.07.017
acute respiratory syndrome coronavirus 2” [All Fields] OR
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imprecise evaluation of viral clearance in patients. Viruses, including “sars cov 2” [All Fields] OR “coronavirus disease 2019” [All Fields]
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Zika
andvirus,
urineEbola virus,
samples ofcytomegalovirus
a volunteer withand humannaso-
positive immunodeficiency
pharyngeal OR “covid19”
(SARS- CoV-2).[All
ArchFields]
PatholOR Lab“covid 19” [All Fields])
Med. 2021;145(1):8- AND (“semen”
9. https://doi.
virus (HIV), have been isolated from
swab. J Endocrinol Invest. 2020;43(12):1819-1822. semen and can be https://doi.
sexually trans- [All Fields] OR “sperm”
org/10.5858/arpa.2020- 0487-LE[All Fields] OR “testis” [All Fields] OR “testes”
6,11,12
org/10.1093/biolr e/ioaa050 44. [All
Rastrelli G, Di Stasi V, Inglese F, et al. Low testosterone levels pre- OR
mitted. Furthermore, some viruses (eg HIV, Zika virus, herpes Fields] OR “testicular” [All Fields] OR “epididymis” [All Fields]
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ducing local inflammation.
Andrology. 9
2021;9:1053–1056 9.Previous
8 studies found that SARS,
https://doi.org/10.1111/andr.13003 ‘seminal
https://doi.org/10.1016/j.jsxm.2020.12.002 1 of the 3 epidemic coronaviruses to emerge in the past 20 years reproduc
66. Schafer L, Mehler L, Hahner A, Walliczek U, Hummel T, Croy I. Sexual
and that shows similar clinical presentations to COVID-19,18 could
desire after olfactory loss: quantitative and qualitative reports
cause orchitis 19 and focal testicular atrophy. 20 Considering the tens
of millions of COVID-19 cases and that men are more vulnerable to 3   |  R
COVID-19 than women, 21-23 it is imperative to determine the effect
of COVID-19 on male reproduction. 24 After rev
Several studies have been performed on this topic. However, and refer
the results are controversial. For example, some researchers have (Figure 1
reported that SARS-CoV-2 was not detected in the male reproduc- study, wi
tive tract, 25-34 while others reported that SARS-CoV-2 RNA was tive tract
found in the semen or testes of COVID-19 patients.35,36 There are ity and 3
also unknown factors regarding COVID-19 and male reproduction. patients.
Orchitis and broad destruction of the testes were found in deceased
COVID-19 patients,35,37 while the pathological characteristics in
survivors remain unknown. In this review, we summarize the current 3.1  | 
research focusing on the effects of COVID-19 on male reproduc- reprodu
tion from the following 3 aspects: detection of SARS-CoV-2 in the
male reproductive tract, determination of the impact of COVID-19 Twelve st
on sperm quality and exploration of pathological changes in the tes- reproduc
tes of COVID-19 patients. We further discuss the discrepancies and sue) and
summarize the unknown topics, which we believe will be helpful for in design
future research. studies re