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 diagnosis 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 (performed 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, relational, 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 development 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 developing COVID-19 and possibly occurring as a consequence of COVID-19. Universal vaccination 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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wileyonlinelibrary.com/journal/andr
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M E TH
D S five sexually active men were thereNine
andOeightyfore identified in the Sex@COVID cohort, among which 25 (2.54%)
COVIDthe
coronavirus
disease caused
by the
severe
acute respibeing tested
as positive
for COVID19. was conducted in the
Since19,
the
first
case of coronavirus
disease
2019
(COVID-19),
caused reported
A systematic
search
of published
studies
ratory
syndrome
coronavirus
2 (SARSCoV2), features 2several
clinby severe
acute
respiratory
syndrome
coronavirus
(SARS-CoV-2),
PubMed and Ovid Embase databases for studies published from
icalwas
phenotypes,
from
mild to
severe
forms:
The “cytokine
reported ranging
in Wuhan,
China,
it has
rapidly
spread
and affected
December 2019 to 18 August 2020 in accordance with PRISMA.38
1,2
storm”
may lead
to the development
of microvascular
thrombotic
more
than
21 million
people worldwide
as of 17 August
2020.1
2.2All |titles
Measures
or abstracts of English-language studies were reviewed for
andSARS-CoV-2
inflammatoryuses
processes,
which in turn promote
progression
to to
angiotensin-converting
enzyme
II (ACE2)
eligibility. Citations and references of the retrieved studies were
possibly
pulmonary
complications.
Someemerged
evidence
also
depressionsources.
were, respectively,
measured
byon
the
GAD- size,
enter lethal
host cells,
similar to
SARS-CoV, which
18has
years
ago. 2 Anxiety
usedand
as additional
There was no
limitation
sample
18
suggested
that induces
even “silent”
asymptomatic forms ofmultiorgan
COVID-19 could
Anxiety
and the
PHQ919performed
(Patient by
COVID-19
respiratory-predominant
dysfunc- 7 (Generalized
and case reports
wereDisorder
included.Scale)
A full-text
review
was
3,4
have
subclinical
involvement
andhepatic
that longterm
Health
Questionnaire),
two questionnaires
for
clinical
use, the
tion,
includingmicrovascular
myocardial, renal,
enteric and
dysfunction,
2 independent
reviewers
(Y.Y. and X.Y.) validated
on studies
that
reported
5,6
3
cardiovascular
sequelae
be expected
in COVID19 patients.
have already
been usedinto
assess
outcomes
of
Meanwhile, which
which coincides
withcould
the tissue
expression
of ACE2.
detection
of SARS-CoV-2
the
male psychological
reproductive tract,
determined
20
Endothelial
dysfunction
been
considered
as the potential
trigger
For
test, scores
≥10quality
are considered
suggestive
several studies
have has
shown
that
ACE2 is expressed
in human
testes COVIDthe 19.
impact
of each
COVID-19
on sperm
and explored
pathologi-
4,5between diffor (eg
the spermatogonia,
onset of more severe
as well
as the
link
anxiety
disorder
depressive
disorder,
respectively.
suggesting that of general
Leydigforms,
cells and
Sertoli
cells),
cal changes
in the
testes and
of COVID-19
patients.
Any
disagreements
7
ferent
comorbidities
associated
with
COVID19
:
Indeed,
COVID19
Erectile
function
was
measured
by
the
IIEF5,
or
Sexual
Health
the testes may be another organ affected by COVID-19.
between reviewers were discussed with a third reviewer
(L.W.).
21,22
6
is by allNumerous
means an viruses
endothelial
in which
manifestafor Men RoB
(SHIM),
shortened,
five-itemand
version
of the
havedisease,
been detected
insystemic
human semen.
Viruses Inventory
The Cochrane
2.0 toolawas
not applicable,
the Newcastle23
tions
of persist
the disease
can and
potentially
be due
to tissue
ischemia
resultIndexwas
of not
Erectile
in of
thethe
clinimay
in semen
last longer
in seminal
fluid
than in other
body International
Ottawa Scale
usedFunction
due to the often
limitedused
scope
cohort
ing fluids
from due
alterations
in endothelial
thrombotic/fibrinolytic
balance.8 of cal setting:
Scores the
21 included
or belowstudies.
are considered suggestive of ED,
to the immune
privilege
of the testes and the contribution
studies among
7,8
Additionally,
endothelial
cells
express
many
of
the
cofactors
used
whereas
scores
22–
25
are
considered
normal.
the blood-testes barrier to resistance to therapeutic agents. Semen
The literature search in PubMed
used the following search terms:
by the
CoV-higher
2 to invade
host
cells.9such as Zika virus, than blood.9,10
maySARSalso have
loads of
viruses,
(“2019 new coronavirus” [All Fields] OR “2019 ncov” [All Fields] OR
Erectile dysfunction
(ED) act
hasasbeen
often considered
a hallmark
Therefore,
the testes may
a reservoir
of virus, which
may cause
10,11
of endothelial
dysfunction,
and
as
such,
a
potential
association
imprecise evaluation of viral clearance in patients. Viruses, including
2.3“sars
| cov
Statistical
analysis
2” [All Fields]
OR “coronavirus disease 2019” [All Fields]
“severe acute respiratory syndrome coronavirus 2” [All Fields] OR
12
between
ED and
COVIDhas also been and
postulated.
Zika virus,
Ebola
virus, 19
cytomegalovirus
human immunodeficiency
OR “covid19” [All Fields] OR “covid 19” [All Fields]) AND (“semen”
Another
interesting
on the
ED and
analysis
was performed
with
statistical
software
R
virus
(HIV),
have beentake
isolated
fromassociation
semen and between
can be sexually
trans- Statistical
[All Fields]
OR “sperm”
[All Fields]
OR the
“testis”
[All Fields]
OR “testes”
6,11,12
COVID19
comes
from
the
shared
risk
factors
for
the
two
condi(version
3.6.2);
statistical
significance
was
set
at
p
<
0.05.
Propensity
Furthermore, some viruses (eg HIV, Zika virus, herpes
mitted.
[All Fields] OR “testicular” [All Fields] OR “epididymis” [All Fields] OR
tions.
Indeed,
severity
of both ED and
matchingfluid”
was used
in orderOR
to “seminal
retrieve two
samples,
simplex
virus
(HSV)and
andprevalence
human papillomavirus)
canCOVIDadhere19toare
or be score
“spermatic
[All Fields]
fluid”matching
[All Fields]
OR “pros7,13 hypertension, obesity, diabetes,
higher
among
men
suffering
from
based
on
age,
body
mass
index
(BMI),
and
GAD7
and
PHQ9
scores,
which may pose a risk for embryonic
internalized by spermatozoa,
tatic secretion” [All Fields] OR “prostatic fluid” [All Fields]
OR “male
13-16
andinfection
history of
speaking, ED is
using
a 1:3 ratio to
improve
reliability
the results.
of
andcardiovascular
cause adverse disease.
reproductiveBroadly
outcomes.
reproductive
tract”
[All Fields]
ORof“male
genital Assessment
tract” [All Fields]).
often considered
a clinical
marker
of a “dysfunctional”
wasin performed
using
Wilk
test (‘2019
of normalOn the other
hand, many
viruses,
such as mumpsphenotype,
virus, HIV and normality
Searches
Ovid Embase
usedthe
theShapirofollowing
terms:
ncov’ OR
7,14 features cardiovascular events at an early age. This
which
often
ity.
Wilcoxon
rank
sum
test
with
continuity
correction
and
have been found to impair semen quality, and they may diHSV,
‘sars cov 2’ OR ‘covid-19’ OR covid19) AND (semen ORFisher's
sperm OR
would
possibly
suggest
subjects with
ED, due
to the underlying
testOR
(onetailed)
were
used toOR
assess
differences
in the numerirectly
interact
with that
spermatozoa
or affect
spermatogenesis
by in- exact
testis
testes
OR
testicular
epididymis
OR ‘spermatic
fluid’ OR
15-17
conditions
whichinflammation.
impair erectile
response,
alsofound
be more
categorical
between
study
groups. Chisquared
Previouscould
studies
thatsusSARS, cal and
ducing local
‘seminal
fluid’ ORvariables
‘prostatic
secretion’
OR ‘prostatic
fluid’
OR ‘male
ceptible
to
contracting
COVID19.
goodnessoffit
test
was
used
to
measure
differences
in
the
preva1 of the 3 epidemic coronaviruses to emerge in the past 20 years
reproductive tract’ OR ‘male genital tract’).
18
The that
present
study
is, toclinical
our knowledge,
the first
one investigatcould lence of ED between study groups. Logistic regression models were
and
shows
similar
presentations
to COVID-19,
20
ing cause
the prevalence
EDfocal
and testicular
the possible
association
betweenthe
EDtens fitted to assess to which extent age, GAD-7 and PHQ-9 scores, BMI,
orchitis 19of
and
atrophy.
Considering
andofCOVID19of
from
real-lifecases
data in
a large
history
function
| of
R ECOVIDS U LT19S affected
A N D erectile
DISCU
S S I O and
N to measure
millions
COVID-19
and
that survey.
men are more vulnerable to and 3
21-23
the
effect
of
age,
BMI,
and
ED
on
the
susceptibility
to
COVID-19.
it is imperative to determine the effect
COVID-19 than women,
2
of COVID-19 on male reproduction. 24
| Several
M ATE
R I A Lhave
S A been
ND M
E TH O DS
studies
performed
on this topic. However,
After reviewing the studies retrieved from the database, citations
and references were added based on a review of the title or abstract
| Power
analysis
the results are controversial. For example, some researchers have 2.4(Figure
1). Fourteen
studies were eligible and were included in this
2.1reported
| Subjects
that SARS-CoV-2 was not detected in the male reproducstudy, with 12 studies detecting SARS-CoV-2 in the male reproductive tract, 25-34 while others reported that SARS-CoV-2 RNA was
In order
an adequate
for thepatients.
present35,36
study,
we are
There
foundtoinretrieve
the semen
or testes sample
of COVID-19
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 reproducOverall, 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 tesparticipated in the Sex@COVID study. All subjects provided intes 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.
Sample
was
based
a 28%ofprevalence
EDsperm
amongqualtive size
tract,
3 calculated
determining
the on
impact
COVID-19ofon
the ity
COVID+group,
using
a
0.8
effect
size
(accounting
for
a
large
efand 3 exploring pathological changes in the testes of COVID-19
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 posthoc 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 tisAccording 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
Etal
Al. .
SANSONE
2
reported having contracted COVID-19 (COVID+), and a matching
1 on| erectile
I NTRO
D U Cmight
TI O N
function
be
10553
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
the first timedisease
the possible
association between
Since
the first casefor
of coronavirus
2019 (COVID-19),
caused
A system
CoV-2 infection prior to filling the Sex@COVID survey (COVID-).
function
and COVID19 in a coronavirus
real-life setting.
Results of our
byerectile
severe acute
respiratory
syndrome
2 (SARS-CoV-2),
PubMed
Descriptive data of the study population are reported in Table 1.
study
agreeinwith
the pathophysiological
mechanisms
ED,
was
reported
Wuhan,
China, it has rapidly
spread andlinking
affected
Decembe
According to propensity score matching, no statistically significant
endothelial
andworldwide
COVID-19. as
By of
performing
propensity
more
than 21dysfunction,
million people
17 August
2020.1
All titles
difference was found for age, GAD-7 and PHQ-9 scores, and BMI
score matching,
removed the possibleenzyme
bias resulting
from to
age
SARS-CoV-2
uses we
angiotensin-converting
II (ACE2)
eligibility
between the two groups. The prevalence of ED was higher in the
andhost
BMI,cells,
factors
which
contributewhich
to both
increased
prevalence
enter
similar
to SARS-CoV,
emerged
18 years
ago. 2
used as a
COVID+group (7/25, 28%) than in the COVID- group (7/75, 9.33%;
and increased
susceptibility to COVID19.15,16 Therefore,
of ED13,14induces
COVID-19
respiratory-predominant
multiorgan
dysfunc-
and case
p-value 0.0274) (Figure 1).
ourincluding
results are
highly suggestive
of the and
role hepatic
of the infection
in the
tion,
myocardial,
renal, enteric
dysfunction,
2 indepe
Logistic regression models confirmed the association of
3
development
the the
sexual
dysfunction
and
the possible
clinical
Meanwhile,
which
coincidesof
with
tissue
expression
ofofACE2.
detection
COVID-19 with ED of COVID-19 on the development of ED (Table 2):
relevance
of have
COVID19 as
an ACE2
additional
risk factor
for thetestes
develseveral
studies
shown
that
is expressed
in human
4,5
opment
of
ED.
Additionally,
considering
the
bidirectional
interac(eg spermatogonia, Leydig cells and Sertoli cells), suggesting that
the impa
between
activity
and psychological
well-being,17 the
thetion
testes
may besexual
another
organ affected
by COVID-19.
6
removal
of the
possible
influence
of anxiety
andsemen.
depression
conNumerous
viruses
have been
detected
in human
Viruses
between
firmed
that
the increased
prevalence
of ED
here
found
is not
only
may
persist
in semen
and last longer
in seminal
fluid
than
in other
body
a
consequence
of
the
psychological
burden
of
lockdown,
but
fluids due to the immune privilege of the testes and the contribution also
of
Ottawa S
While age, BMI, and psychological health scores failed to reach statistical significance, history of COVID-19 was highly significant, resulting in a 5.66 odds ratio [95% confidence interval: 1.50–24.01] of
having ED.
Since ED could be a valid clinical marker of several underlying
and unaccounted conditions, such as diabetes and hypertension, we
also measured in the same sample the likelihood of having a selfreported history of COVID-19 following a diagnosis of ED. Logistic
regression models adjusted for age and BMI (Table 3) showed a significant association between ED and COVID-19, with a 5.27 odds
ratio [95% CI: 1.49–20.09].
4
|
DISCUSSION
The large majority of the studies investigating the effects of
COVID-19 on male sexual and reproductive health have focused
on fertility and its preservation, 24-30 and to the present date, there
seems to be no definite evidence of the presence of SARS- CoV-2 in
seminal fluid31,32 ; however, there is reason to suspect that sexual
quality of life and function might also be impaired as a consequence
of COVID-19.12,33,34 While of course this is of relative importance
to patients in intensive care units, the possible long-term effects
7,8
to other,
bona fide
factors,
among
which
Semen
theprominently
blood-testesdue
barrier
to resistance
to organic
therapeutic
agents.
9,10
endothelial
dysfunction
the most
On blood.
the other
may
also have higher
loads ofisviruses,
such likely
as Zikaculprit.
virus, than
cal chang
The Coch
studies a
The li
(“2019 ne
hand, there
another
explanation:
ED iswhich
a well-may
recognized
Therefore,
the istestes
mayplausible
act as a reservoir
of virus,
cause
11
surrogate
marker
of
systemic
health,
and
therefore,
ED
patients
imprecise evaluation of viral clearance in patients. Viruses, including
“severe a
could
already
carry cytomegalovirus
several underlying
unexplored
risk factors,
Zika
virus,
Ebola virus,
andand
human
immunodeficiency
such
as dyslipidemia,
diabetes,
hypertension,
which could
virus
(HIV),
have been isolated
fromand
semen
and can be sexually
trans-in-
OR “covi
6,11,12
crease
the Furthermore,
likelihood of contracting
19.Zika
Hence,
weherpes
also insome virusesCOVID(eg HIV,
virus,
mitted.
vestigated
whether
subjects
with
ED,
owing
to
the
worse
systemic
simplex virus (HSV) and human papillomavirus) can adhere to or be
[All Field
7,13more at risk of developing COVID-19.
health,11 could
possibly be
which may pose a risk for embryonic
internalized
by spermatozoa,
Based and
on our
preliminary
results, EDoutcomes.
and COVID-19 seem to be
infection
cause
adverse reproductive
strongly
associated,
increasing
thevirus,
chances
deOn the other
hand, with
manyCOVIDviruses,19
such
as mumps
HIVof
and
7,14
veloping
ED
and
ED
being
a
marker
of
increased
susceptibility
have been found to impair semen quality, and they may di-to
HSV,
infection.
While
adequately
studies are needed,
we
rectly
interact
withmore
spermatozoa
or tailored
affect spermatogenesis
by in-
“sars cov
[All Field
“spermat
tatic secr
reproduc
Searches
‘sars cov
testis OR
ducing local inflammation.15-17 Previous studies found that SARS,
‘seminal
1 of the 3 epidemic coronaviruses to emerge in the past 20 years
reproduc
and that shows similar clinical presentations to COVID-19,18 could
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
TA B L E 1 Characteristics of the study population
COVID+
(n = 25)
Age (years)
2
COVID(n = 75)
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
a
tive tract, 25-34 while others reported that SARS-CoV-2 RNA was
tive tract
a
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.
p-value
39.00 [29.00, 45.00] 42.00 [32.50, 49.00] 0.142
BMI (kg/m )
22.65 [20.83, 23.74] 22.74 [20.98, 24.53] 0.266
GAD−7 score
4.00 [2.00, 6.00]
PHQ−9 score
Erectile
dysfunction
5.00 [3.00, 6.00]
7 (28%)
4.00 [2.00, 5.00]
0.741a
4.00 [2.00, 5.00]
a
7 (9.33%)
0.873
0.027b
Statistically significant values highlighted in bold.
All data expressed as median [interquartile range] except prevalence of
erectile dysfunction, expressed as n (%).
Abbreviations: BMI, body mass index; GAD-7, Generalized Anxiety
Disorder Scale;HQ-9, Patient Health Questionnaire.
a
After rev
Several studies have been performed on this topic. However,
Wilcoxon rank sum test with continuity correction; bFisher's exact test
(one-tailed).
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
research focusing on the effects of COVID-19 on male reproduc-
3.1 |
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
F I G U R Ethe
1 unknown
Prevalence
of erectile
in the
summarize
topics,
which dysfunction
we believe will
be COVID+
helpful for
and COVID− groups
future research.
sue) and
in design
studies re
| |
2
41056
1
SANSONE
Et
SANSONEYAO
etAl
al..et Al .
|
TA B L E 2 Results of logistic regression
I NTRO D U C TI O N
Estimate
Std. error
Odds
2 |ratioM E TH O Dmodels
S
for erectile dysfunction (ED)
[95% CI]
p-value
Intercept
−9.607 disease 2019
3.216
0.003
Since the first case of coronavirus
(COVID-19),
caused
by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
according to age, body mass index (BMI),
0.00
A systematic search psychological
of publishedhealth,
studiesand
was
conducted
selfreferred in the
[0.00–
0.02]and Ovid Embase
history of
COVID-19.
9: Patient
PubMed
databases
forPHQstudies
published from
Age
(years)
0.062 it has rapidly
0.027
was
reported in Wuhan, China,
spread and0.023
affected
Health
Questionnaire
and GAD7: PRISMA.38
1.06
[1.01–1.13]
December
2019 to 18
August
2020 in accordance
with
BMI
0.143
0.106
0.178
more than 21 million people
worldwide as
of 17 August
2020.1
1.15
[0.93–or
1.43]
All titles
abstracts of English-language studies were reviewed for
Generalized Anxiety Disorder Scale
GAD−7
score
0.114
0.193
0.556 to
SARS-CoV-2
uses angiotensin-converting
enzyme II (ACE2)
1.12
[0.77–1.66]
eligibility.
Citations and references of the retrieved studies were
2
used[0.88–
as additional
sources. There was no limitation on sample size,
1.16
1.55]
COVID-19
induces respiratory-predominant
multiorgan 0.013
dysfuncPrevious
COVID−19
1.734
0.694
tion, including myocardial, renal, enteric and hepatic dysfunction,
and case reports were included. A full-text review was performed by
5.66
[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
enter score
host cells, similar to SARS-CoV,
which 0.143
emerged 18 years
PHQ−9
0.148
0.301ago.
several studies have shown that ACE2 is expressed in human testes
the impact of COVID-19 on sperm quality and explored pathologi5,53
4,5
TA (eg
B L Espermatogonia,
3 Results of logistic
regression
models
for
COVID
and
involving
same
cytokines
could
be promoted
by the
Leydig cells and Sertoli cells), suggesting that
cal
changesthe
in the
testes
of COVID-19
patients.
Any disagreements
according
to
age,
body
mass
index
(BMI),
and
erectile
dysfunction
hypogonadal
state
encountered
in
affected
patients.
The
immuthe testes may be another organ affected by COVID-19.
between reviewers were discussed with a third reviewer
(L.W.).
(ED)
6
could
potentially
affect
penile vessels,
Numerous viruses have been detected in human semen. Viruses nothrombosis
The Cochrane
RoB
2.0 tool was
notthe
applicable,
and the triggerNewcastledysfunction—
therefore
function
may persist in semen and lastStd.
longer in seminal fluid than in other body ing endothelial
Ottawa Scale
was not used
due to impairing
the limitedvascular
scope of
the cohort
error ofpvalue
ratio
[95% CI] of and studies
promoting
progression
to studies.
more severe forms of sexual dysfluids due to the Estimate
immune privilege
the
testesOdds
and the
contribution
among
the included
54,55
7,8
Other
cardiovascular
complications
of COVIDfunction.
the blood-testes barrier
to therapeutic
agents.
The literature search in PubMed
used the following
search19,
terms:
Intercept
1.910 to resistance
2.194 0.384
6.75 [0.11–
661.99]Semen
56,57
such(“2019
as cardiomyopathy
and[All
myocarditis,
in- OR
new coronavirus”
Fields] OR “2019could
ncov”also
[All be
Fields]
volved
in the
pathogenesis
ofsyndrome
ED even after
the end2”
of[All
the Fields]
acute OR
Therefore,
the
testes
may
act
as
a
reservoir
of
virus,
which
may
cause
“severe
acute
respiratory
coronavirus
BMI
−0.096
0.089 0.281
0.91 [0.76–1.07]
5,6
potentially
becoming
longterm cardiovascular
sequelae.
imprecise evaluation of viral clearance in patients. Viruses, including phase,
“sars
cov 2” [All
Fields] OR
“coronavirus
disease 2019”
[All Fields]
9,10
may
also have higher
loads of0.021
viruses,0.197
such as Zika
Age
(years)
−0.027
0.97virus,
[0.93–than
1.01]blood.
Presence of ED
1.662
0.652
0.011
5.27 [1.49–20.09]
couldOR
contribute
to impaired
erectile
Zika virus, Ebola virus, cytomegalovirus and human immunodeficiency Other
ORpotential
“covid19”factors
[All Fields]
“covid 19”
[All Fields])
ANDfunc(“semen”
58,59
in COVID19 patients,
such
as pulmonary
fibrosis
virus (HIV), have been isolated from semen and can be sexually trans- tion[All
Fields] OR
“sperm” [All
Fields]
OR “testis”
[All Fields] causing
OR “testes”
60,61
6,11,12
believe
that
our Furthermore,
study highlights
theviruses
possible
sexual
in theOR
penile
vascular
or “epididymis”
anosmia and[All
ageusia,
some
(egrelevance
HIV, Zikafor
virus,
herpes hypoxia
mitted.
[All Fields]
“testicular”
[Allbed,
Fields] OR
Fields] OR
62,63
medicine
and
andrology
of
COVID19
spectrum
of
disease
and
its
both
manifestations
of
COVID19
with
possible
negative
simplex virus (HSV) and human papillomavirus) can adhere to or be
“spermatic fluid” [All Fields] OR “seminal fluid” [All Fields] ORef“pros64- 67
7,13
short
and long-by
term
health consequences.
on secretion”
sexual health.
these factors
could
possibly
which may pose a risk for embryonic fects
internalized
spermatozoa,
tatic
[All Fields]While
OR “prostatic
fluid” [All
Fields]
OR “male
There is and
a solid
pathogenetic
background
for the mechanisms
havereproductive
a minor influence
when
considered
the[All
likely
infection
cause
adverse reproductive
outcomes.
tract” [All
Fields]
OR “maleindividually,
genital tract”
Fields]).
12
through
which
COVID19
could
affect
erectile
function.
Many
presence
of
most,
if
not
all,
of
them
at
the
same
time
could
easily
On the other hand, many viruses, such as mumps virus, HIV and
Searches in Ovid Embase used the following terms: (‘2019 ncov’ OR
machineries
through
SARSCoV2 invades
thecov
progression
from a subclinical
to AND
an overt
formOR
of sexual
been which
found to
impair
semen
quality,the
andhost
theycells
may di- allow
HSV,7,14 have
‘sars
2’ OR ‘covid-19’
OR covid19)
(semen
sperm OR
68,69
have
been
identified:
The
virus
uses
angiotensinconverting
endysfunction.
Considering
the
subclinical,
yet
nonnegligible,
rectly interact with spermatozoa or affect spermatogenesis by intestis OR testes OR testicular OR epididymis OR ‘spermatic fluid’ OR
4
15-17to the cells, and primes the spike
zyme
2 (ACE2)
an entry point
reported
in asymptomatic
subjects,
we‘male
Previous studies found that SARS, cardiopulmonary
ducing
local as
inflammation.
‘seminal fluid’ damage
OR ‘prostatic
secretion’
OR ‘prostatic
fluid’ OR
protein,
which
facilitates
viral
entry
into
target
cells,
by
employing
speculate
that
the
same
progression
from
subclinical
to
an
overt
1 of the 3 epidemic coronaviruses to emerge in the past 20 years
reproductive tract’ OR ‘male genital tract’).
35
18
theand
transmembrane
protease,
serine
2 TMPRSS2.
The SARScould sexual dysfunction could also occur in subjects with “silent” forms
that shows similar
clinical
presentations
to COVID-19,
CoV2 therefore
shows
sometesticular
similarities
with 20another
coronavicause
orchitis 19
and focal
atrophy.
Considering
the tens of COVID-19 in the presence of additional risk factors—being the
36,37
rus,of millions
namely
SARS- CoV,cases
the and
virusthat
strain
for the to proverbial
breaks
the
3 | straw
R E Sthat
U LT
S AN
Dcamel's
D I S Cbreak.
USSION
of COVID-19
menresponsible
are more vulnerable
21-23
SARS
outbreak
occurring
2003–
2004. 37-39 to
Since
adult Leydig
Based on the presented evidence and on similarities to previit is imperative
determine
the effect
COVID-19
than
women,in
24
cells
express
ACE2,
testicular
involvement
due
to
COVID19
has
ous
coronavirus
diseases,
ED could
therefore
bethe
both
a short-term
After
reviewing
the studies
retrieved
from
database,
citations
of COVID-19 on male reproduction.
40
41
been hypothesized
and
a
longterm
complication
of
COVID19.
The
potential
and
confirmed
in
autopsy
reports.
Also,
at
Several studies have been performed on this topic. However,
and references were added based on a review of the titleassociaor abstract
between
and COVID19were
might
increase
of the
least
caseare
of acute
orchitis For
following
SARSCoV2 infectionhave tion(Figure
theone
results
controversial.
example,
some
researchers
1). ED
Fourteen
studies
eligible
andawareness
were included
in this
42
importance
of
personal
protective
equipment,
such
as
masks,
and
hasreported
been reported.
The
testicular
injury
reported
in
these
studies
that SARS-CoV-2 was not detected in the male reproducstudy, with 12 studies detecting SARS-CoV-2 in the male reproducin a harm reduction
foronlongtermqualcould
be25-34
a consequence
of reported
alterationsthat
in the
coagulative
sta-was social
while others
SARS-CoV-2
RNA
tivealso
tract,
tivedistancing
tract, 3 determining
the impactperspective
of COVID-19
sperm
43
tus,found
resulting
in development
of ischemia
at a microvascular
There are
in the
semen or testes
of COVID-19
patients.35,36level.
Independently of the etiology, testicular damage can possibly lead
also unknown factors regarding COVID-19 and male reproduction.
to the development of a form of hypergonadotropic hypogonadOrchitis and broad destruction of the testes were found in deceased
ism 44- 48 : As testosterone
modulates endothelial function,49 the
COVID-19 patients,35,37 while the pathological characteristics in
possible effects of COVID-19 on erection could also be indirectly
survivors remain unknown. In this review, we summarize the current
due to impaired testosterone secretion from the affected testis,
research focusing on the effects of COVID-19 on male reproducbesides the known direct effects of testosterone in male sexual
tion from the following 3 aspects: detection of SARS-CoV-2 in the
response. 50 Additionally, as higher testosterone levels are also asmale reproductive tract, determination of the impact of COVID-19
sociated with lower levels of pro-inflammatory cytokines such as
on sperm quality and exploration of pathological changes in the testumor necrosis factor alpha (TNF- α), interleukins (IL- 6 and IL-1β),
tes of COVID-19 patients. We further discuss the discrepancies and
and higher levels of anti-inflammatory cytokines (such as IL-10), 51
summarize the unknown topics, which we believe will be helpful for
the “immunothrombotic” mechanism described for COVID-1952
future research.
70
consequences.
The use
of masks changes
as devices
for testes
the prevention
ity and 3 exploring
pathological
in the
of COVID-19
of sexual dysfunctions is perhaps a bit stretched, but at present
patients.
we believe that this could also possibly be an additional strategy to
promote the use of personal protective equipment—as people have
already posted on Twitter, using the hashtag “#MaskUpToKeepItUp.”
3.1 | Detection of COVID-19 in the male
reproductive tract
Additionally, subjects with a sudden onset or worsening of ED might
also consider precautionary quarantine or nasopharyngeal swab, as
COVID-19 might act as a potential initiating trigger for the onset of
Twelve studies investigated the presence of SARS-CoV-2 in the male
erectile impairment, or an aggravating factor for its progression to
reproductive tract (eg semen, prostatic secretion or testicular tismore severe forms.
sue) and are shown in Table 1. Most studies were cross-sectional
Likewise, subjects with ED should consider their erectile imin design and included mainly Chinese subjects. In brief, ten of 12
pairment as a sign of possible underlying conditions which could
studies reported that none of the participants had SARS-CoV-2 RNA
|
|
SANSONE et
Etal
Al. .
SANSONE
2
increase the likelihood of suffering from COVID-19. Therefore, the
1 R E| F EIRNTRO
E N C E SD U C TI O N
importance of investigating the possible causes of ED becomes of
1. Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP. The trinity of
COVID19: immunity,
inflammation
and (COVID-19),
intervention. caused
Nat Rev
Since the
first case
of coronavirus
disease 2019
Immunol. 2020;20(6):363-374. https://doi.org/10.1038/s4157
by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
7- 020- 0311-8
was2.reported
Wuhan,
China,19
it cytokine
has rapidly
spread
and affected
Jose RJ,in
Manuel
A. COVIDstorm:
the interplay
between
more than
21 million
worldwide
of 17
August
2020.1
inflammation
andpeople
coagulation.
Lancetas
Respir
Med.
2020;8(6):e46e47. https://doi.org/10.1038/s4157
7- 0200311-8 II (ACE2) to
SARS-CoV-2
uses angiotensin-converting
enzyme
3. Oran DP, Topol EJ. Prevalence of asymptomatic SARS-CoV-2 2inenter host cells, similar to SARS-CoV, which emerged 18 years ago.
fection: a narrative review. Ann Intern Med. 2020;173(5):362-367.
COVID-19
induces respiratory-predominant
multiorgan dysfunchttps://doi.org/10.7326/M203012
tion,4. including
myocardial,
enteric
hepatic
dysfunction,
Long QX,
Tang XJ, renal,
Shi QL,
et al.and
Clinical
and
immunological assessment
of tissue
asymptomatic
SARS2 3infections.
Nat
Meanwhile,
which coincides
with the
expression
of CoVACE2.
Med.
2020;26(8):1200-1204.
https://doi.org/10.1038/s4159
several studies have shown that ACE2 is expressed in human testes
1- 020- 0965-6
4,5
suggesting
that
(eg 5.
spermatogonia,
cells
and
Sertoli
cells),
Liu PP, Blet A,Leydig
Smyth D,
Li H.
The
science
underlying
COVID-19:
imthe testes
may be
organ affected
byCirculation.
COVID-19.
plications
foranother
the cardiovascular
system.
2020;142(1):6878. https://doi.org/10.1161/CIRCU
LATIO
NAHA.120.047549
Numerous
viruses have been detected
in human
semen.6 Viruses
6. Vittori A, Lerman J, Cascella M, et al. COVID-19 pandemic acute remay persist in semen and last longer in seminal fluid than in other body
spiratory distress syndrome survivors: pain after the storm? Anesth
fluids due
to the
immune privilege
the testes and the contribution of
Analg.
2020;131(1):117119.of https://doi.org/10.1213/ANE.00000
the blood-testes
barrier to resistance to therapeutic agents.7,8 Semen
00000 004914
9,10
I, Limonta
Mahal LK,
Hobman
Endothelium
may7.alsoBernard
have higher
loads D,
of viruses,
such
as ZikaTC.
virus,
than blood.infection and dysregulation by SARS-CoV-2: evidence and caveats in
Therefore, the testes may act as a reservoir of virus, which may cause
COVID-19. Viruses. 2021;13(1):29. https://doi.org/10.3390/v1301
imprecise
evaluation of viral clearance in patients. Viruses, including
0029
Zika8.virus,
Ebola
virus, cytomegalovirus
and
Libby
P, Luscher
T. COVID-19 is, in
thehuman
end, animmunodeficiency
endothelial disease.
Eur have
Heartbeen
J. 2020;41(32):30383044.
virus (HIV),
isolated from semen
and https://doi.org/10.1093/
can be sexually transeurheartj/ehaa623
mitted.6,11,12 Furthermore, some viruses (eg HIV, Zika virus, herpes
9. Pons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the
simplexcornerstone
virus (HSV)ofand
human
papillomavirus)
adhere
or be
organ
dysfunction
in severecan
SARSCoV-2toinfection.
7,13
which
may pose a risk for embryonic
internalized
by spermatozoa,
Crit Care.
2020;24(1): 353.
https://doi.org/10.1186/s1305
4- 02003062
-7
infection
and cause
adverse reproductive outcomes.
10. Guay AT. ED2: erectile dysfunction = endothelial dysfunction.
On the other hand, many viruses, such as mumps virus, HIV and
Endocrinol Metab Clin North Am. 2007;36(2):453- 463. https://doi.
have been found to impair semen quality, and they may diHSV,7,14org/10.1016/j.ecl.2007.03.007
rectly
with
or affect
by in11. interact
Jannini EA.
SMspermatozoa
= SM: The interface
of spermatogenesis
systems medicine and
sex15-17non-communicable diseases in a gendermedicine
for facing
Previous studies found that SARS,
ducing ual
local
inflammation.
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
org/10.1016/j.sxmr.2017.04.002
18
and
shows A,
similar
clinical
presentations
COVID-19,
12.that
Sansone
Mollaioli
D, Ciocca
G, et al.to
Addressing
malecould
sexual
19
20
cause orchitis
and focalhealth
testicular
atrophy.
the tens J
and reproductive
in the
wake of Considering
COVID-19 outbreak.
Endocrinol
Investig.cases
2021;44(2):223231.are
https://doi.org/10.1007/
of millions
of COVID-19
and that men
more vulnerable to
s40618- 020- 01350
-1
21-23
it is imperative to determine the effect
COVID-19 than women,
13. Romanelli F, Sansone A, Lenzi A.
Erectile dysfunction in aging male.
24
of COVID-19
on male
reproduction.
Acta Biomed.
2010;81(Suppl
1):89-94.
Several
studies
have G,
been
performed
this topic.
14.
Mollaioli
D, Ciocca
Limoncin
E, et al.onLifestyles
andHowever,
sexuality in
Reprod
men
and
women:
the
gender
perspective
in
sexual
medicine.
the results are controversial. For example, some researchers have
Biol Endocrinol. 2020;18(1): 10. https://doi.org/10.1186/s1295
reported that SARS-CoV-2 was not detected in the male reproduc8- 0190557-9
25-34
while
others
reported
SARS-CoV-2
RNAforwas
tive
15.tract,
Mahase E.
Covid19: Why
are age that
and obesity
risk factors
seri35,36
There
are
found in
the
semen
or
testes
of
COVID-19
patients.
ous disease? BMJ. 2020;371: m4130. https://doi.org/10.1136/bmj.
m4130 factors regarding COVID-19 and male reproduction.
also unknown
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.
while the pathological characteristics
in
COVID-19
patients, https://doi.org/10.3390/jcm90
2020;9(8):2511.
82511
survivors
remainD,unknown.
In Ciocca
this review,
summarize
the current
17. Mollaioli
Sansone A,
G, et we
al. Benefits
of sexual
activity
onfocusing
psychological,
relational,
healthon
during
COVID-19
research
on the
effectsand
of sexual
COVID-19
malethe
reproducbreakout. 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
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
on sperm
and exploration
pathological
changes
in the
tesof quality
the Generalized
Anxietyof Disorder
Screener
(GAD7) in
the
general population.
Medfurther
Care. discuss
2008;46(3):266274. https://doi.
tes of COVID-19
patients. We
the discrepancies
and
org/10.1097/MLR.0b013e318160d093
paramount importance in times like these: Identifying and treating potential comorbidities would have potentially beneficial effects on erectile function, while at the same time reducing the
risk of contracting SARS- CoV-2 or developing more severe forms
of COVID-19.
The present study has several limitations, including its retrospective nature, the recall bias associated with the use of online
questionnaires, and the inclusion of diagnosis of COVID-19 based on
the response to the survey, rather than on nasopharyngeal swabs.
Additionally, as the survey did not investigate the potential comorbidities (such as diabetes, endocrine disorders, and hypertension
13,50,54,71-73
), treatments (such as anti-depressants
styles (such as smoking
14,54,74
54,71
), and life-
) affecting sexual health, these find-
ings only provide preliminary evidence of the association between
COVID-19 and erectile dysfunction. However, at the time of the first
Italian lockdown here explored, swabs were rarely available, and an
online survey was the most reliable way to obtain information on
a large cohort of patients without breaking restrictions. While our
study could not include such data, based on the study design, more
studies adequately tailored to investigate the endocrine function,
most importantly testosterone, and penile vascular dynamics in patients with a history of COVID-19 are needed to provide definite
evidence; however, at present our findings, no matter how limited,
are highly suggestive of a potential long-term risk for male sexual
function following COVID-19.
AC K N OW L E D G M E N T S
None.
C O N FL I C T S O F I N T E R E S T
The authors declare no competing interests for the present study.
AU T H O R ' S C O N T R I B U T I O N S
Conceptualization, AS, DM and EAJ; data curation, AS and DM; formal analysis, AS and DM; investigation, AS, DM, GC, EL, EC; methodology, AS and DM.; project administration and supervision, EAJ;
validation, EAJ; visualization, AS; writing—original draft, AS and DM;
writing—review and editing, GC, EL, EC, GB and EAJ. We attest that
all authors contributed significantly to the creation of this manuscript. We confirm that the order of authors listed in the manuscript
has been approved by all named authors. All authors have read and
agreed to the published version of the manuscript.
ORCID
Andrea Sansone
https://orcid.org/0000-0002-1210-2843
Daniele Mollaioli
https://orcid.org/0000-0001-5947-3310
Giacomo Ciocca
https://orcid.org/0000-0002-4256-1776
Elena Colonnello
https://orcid.org/0000-0002-0081-7163
Giancarlo Balercia
https://orcid.org/0000-0003-1286-1521
Emmanuele A. Jannini
https://orcid.org/0000-0002-5874-039X
10575
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ity and 3
patients.
3.1 |
reprodu
Twelve st
reproduc
sue) and
summarize the unknown topics, which we believe will be helpful for
in design
future research.
studies re
| |
2
61058
19. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief
1 | I NTRO D U C TI O N
depression severity measure. J Gen Intern Med. 2001;16(9):606613. https://doi.org/10.1046/j.1525-1497.2001.016009606.x
case of
2019
(COVID-19),
caused
20. Since
Lai J,the
Mafirst
S, Wang
Y, coronavirus
et al. Factorsdisease
associated
with
mental health
among
health care
workerscoronavirus
exposed to2 coronavirus
byoutcomes
severe acute
respiratory
syndrome
(SARS-CoV-2),
disease 2019. JAMA Netw Open. 2020;3(3):e203976. https://doi.
was reported in Wuhan, China, it has rapidly spread and affected
org/10.1001/jamanetworkopen.2020.3976
than
million
worldwide
of male
17 August
2020.1
21. more
Corona
G, 21
Jannini
EA, people
Maggi M.
Inventoriesasfor
and female
SARS-CoV-2
uses angiotensin-converting
enzyme250.
II https://
(ACE2) to
sexual dysfunctions.
Int J Impot Res. 2006;18(3):236doi.org/10.1038/sj.ijir.3901410
enter
host cells, similar to SARS-CoV, which emerged 18 years ago. 2
22. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM.
COVID-19 induces respiratory-predominant multiorgan dysfuncDevelopment and evaluation of an abridged, 5-item version of
tion,
including myocardial,
renal, Function
enteric and
dysfunction,
the International
Index of Erectile
(IIEF-hepatic
5) as a diagnostic
which
coincides
the tissue
of ACE2.3 Meanwhile,
tool for
erectile with
dysfunction.
Int Jexpression
Impot Res. 1999;11(6):319326.
https://doi.org/10.1038/sj.ijir.3900472
several
studies have shown that ACE2 is expressed in human testes
23. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick
J, Mishra
(eg spermatogonia, Leydig cells and Sertoli cells),4,5 suggesting that
A. The international index of erectile function (IIEF): a multidithe
testes may
be for
another
organ affected
COVID-19. Urology.
mensional
scale
assessment
of erectilebydysfunction.
Numerous viruses
have been detected in human semen.6 Viruses
1997;49(6):822830. https://doi.org/10.1038/sj.ijir.3901410
24. may
Song
C, Wang
Y, Li and
W, et
Absence
of 2019
novel
coronavirus
persist
in semen
lastal.longer
in seminal
fluid
than
in other body
in semen and testes of COVID-19 patientsdagger. Biol Reprod.
fluids due to the immune privilege of the testes and the contribution of
2020;103(1):4-6. https://doi.org/10.1093/biolre/ioaa050
7,8
Semen
blood-testes
barrier
tooftherapeutic
agents.
25. the
Pan
F, Xiao X, Guo
J, et to
al. resistance
No evidence
severe acute
respiratory
9,10
may
also have
higher loads
ofsemen
viruses,
asrecovering
Zika virus, from
than blood.
syndromecoronavirus
2 in
ofsuch
males
coronavirus disease
2019.may
Fertil
2020;113(6):1135Therefore,
the testes
actSteril.
as a reservoir
of virus, 1139.
whichhttps://
may cause
doi.org/10.1093/biolre/ioaa050
imprecise evaluation of viral clearance in patients. Viruses, including
26. Paoli D, Pallotti F, Colangelo S, et al. Study of SARS-CoV-2 in semen
Zika
virus,
humannasoimmunodeficiency
andvirus,
urineEbola
samples
ofcytomegalovirus
a volunteer withand
positive
pharyngeal
virus
(HIV),
have
been
isolated
from
semen
and
can
be https://doi.
sexually transswab. J Endocrinol Invest. 2020;43(12):1819-1822.
6,11,12
org/10.1093/biolr
e/ioaa050
Furthermore, some viruses (eg HIV, Zika virus, herpes
mitted.
27. Holtmann N, Edimiris P, Andree M, et al. Assessment of SARS-CoV-2
simplex virus (HSV) and human papillomavirus) can adhere to or be
in human semen-a cohort study.
Fertil Steril. 2020;114(2):233-238.
internalized
by spermatozoa,7,13 which may pose a risk for embryonic
https://doi.org/10.1016/j.fertnstert.2020.05.028
andW,cause
reproductive
outcomes.
28. infection
Ma L, Xie
Li D,adverse
et al. Evaluation
of sexrelated hormones and
semen
characteristics
in
reproductiveaged
COVID19HIV
pa- and
On the other hand, many viruses, such asmale
mumps
virus,
tients.
7,14 J Med Virol. 2021;93(1):456- 462. https://doi.org/10.1002/
have been found to impair semen quality, and they may diHSV,
jmv.26259
rectly
interact
with spermatozoa or affect spermatogenesis by in29. Guo L, Zhao S, Li W, et al. Absence of SARS-CoV-2 in semen of a
15-17
Previous
studies found
that SARS,
ducing
local
inflammation.
COVID-19 patient cohort. Andrology.
2021;9(1):4247. https://doi.
org/10.1111/andr.12848
1 of the 3 epidemic coronaviruses to emerge in the past 20 years
30. Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical characteristics18and
and that shows similar clinical presentations to COVID-19, could
results of semen
tests among men with coronavirus disease 2019.
cause
orchitis 19 and focal testicular atrophy. 20 Considering the tens
JAMA Network Open. 2020;3(5):e208292. https://doi.org/10.1001/
ofjaman
millions
ofkopen.2020.8292
COVID-19 cases and that men are more vulnerable to
etwor
21-23
31. COVID-19
Corona G,than
Baldiwomen,
E, Isidori
AM,
al. SARS-CoV2 infection,the
male
it isetimperative
to determine
effect
fertility and sperm cryopreservation:
of COVID-19 on male reproduction. 24 a position statement of the
Italian Society of Andrology and Sexual Medicine (SIAMS) (Societa
Several studies have been performed on this topic. However,
Italiana di Andrologia e Medicina della Sessualita). J Endocrinol
the
results
are controversial.
example, some researchers8-have
Invest.
2020;43(8):11531157.Forhttps://doi.org/10.1007/s4061
020- 01290
-wSARS-CoV-2 was not detected in the male reproducreported
that
32. tive
Paoli
D, Pallotti
25-34 F, Turriziani O, et al. SARS- CoV-2 presence in semwhile others reported that SARS-CoV-2 RNA was
tract,
inal fluid: Myth or reality. Andrology. 2021;9(1):23-26. 35,36
https://doi.
There are
found in the semen or testes of COVID-19 patients.
org/10.1111/andr.12825
unknown
factors
reproduction.
33. also
Li G,
Tang D,
Song regarding
B, et al. COVID-19
Impact of and
the male
COVID19 pandemic and
on partner
relationships
andtestes
sexual
andfound
reproductive
Orchitis
broad destruction
of the
were
in deceased
35,37 online survey study. J Med Internet Res.
health: Crosssectional,
while the pathological characteristics in
COVID-19
patients,
2020;22(8):e20961. https://doi.org/10.2196/20961
survivors remain unknown. In this review, we summarize the current
34. Panzeri M, Ferrucci R, Cozza A, Fontanesi L. Changes in sexualresearch
focusing
the relationship
effects of COVID-19
male19reproducity and quality
of on
couple
during the on
COVIDlockdown.
Psychol. 2020;11:565823.
https://doi.org/10.3389/
tion
fromFront
the following
3 aspects: detection
of SARS-CoV-2 in the
fpsyg.2020.565823
male
reproductive tract, determination of the impact of COVID-19
35. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensinon sperm quality and exploration of pathological changes in the tesconverting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular
tes
of COVID-19
further discuss
the discrepancies
mechanisms
andpatients.
potentialWe
therapeutic
target. Intensive
Care Med. and
2020;46(4):586590. https://doi.org/10.1007/s0013
4- 02005985 for
summarize
the unknown
topics, which we believe will
be helpful
9
future research.
SANSONEYAO
etAl
al..et Al .
SANSONE
Et
36. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell
2 | M E TH O D S
entry depends on ACE2 and TMPRSS2 and is blocked by a clinically
proven protease inhibitor. Cell. 2020;181(2):271-280 e8. https://
Adoi.org/10.1016/j.cell.2020.02.052
systematic search of published studies was conducted in the
37. PubMed
Rabaan AA,
Ahmed
SH, Haque
S, etfor
al. studies
SARS-CoV2, SARS-from
and AlOvid
Embase
databases
published
CoV, and MERS-COV: a comparative overview. Infez Med.
December 2019 to 18 August 2020 in accordance with PRISMA.38
2020;28(2):174-184.
titles
or Zheng
abstracts
English-language
studies
were reviewed
38. All
Chan
KS,
JP, of
Mok
YW, et al. SARS:
prognosis,
outcome for
eligibility.
Citations
and references
of the retrieved
studies were
and sequelae.
Respirology.
2003;8(s1):S36S40. https://doi.
org/10.1046/j.14401843.2003.00522.x
used
as additional sources.
There was no limitation on sample size,
39. Gralinski LE, Bankhead A 3rd, Jeng S, et al. Mechanisms of severe
and case reports were included. A full-text review was performed by
acute respiratory syndrome coronavirus-induced acute lung injury.
2MBio.
independent
reviewers13.
(Y.Y.https://doi.org/10.1128/mBio.00271
and X.Y.) on studies that reported the
2013;4(4):e00271detection
of SARS-CoV-2 in the male reproductive tract, determined
-13
40. the
Douglas
GC,
MK, on
Hedger
MP,quality
et al. The
angiotensinimpact
ofO'Bryan
COVID-19
sperm
andnovel
explored
pathologiconverting enzyme (ACE) homolog, ACE2, is selectively expressed
cal changes in the testes of COVID-19 patients. Any disagreements
by adult Leydig cells of the testis. Endocrinology. 2004;145(10):4703between
reviewers were discussed with
4711. https://doi.org/10.1210/en.20040443a third reviewer (L.W.).
Cochrane
2.0 tool
was
applicable,
and the
Newcastle41. The
Yang
M, Chen RoB
S, Huang
B, et
al. not
Pathological
findings
in the
testes of COVID19 not
patients:
Eur Urol
Focus.
Ottawa
Scale was
used clinical
due to implications.
the limited scope
of the
cohort
2020;6(5):1124-1129. https://doi.org/10.1210/en.2004- 0443
studies among the included studies.
42. La Marca A, Busani S, Donno V, Guaraldi G, Ligabue G, Girardis
literature
search
PubMedpresentation
used the following
search
M.The
Testicular
pain
as anin unusual
of COVID19: terms:
a
(“2019
new coronavirus”
[All
Fields]
OR “2019
ncov”
[All Online.
Fields] OR
brief review
of SARS-CoV2 and
the testis.
Reprod
Biomed
2020;41(5):903906. https://doi.org/10.1016/j.rbmo.2020.07.017
“severe
acute respiratory
syndrome coronavirus 2” [All Fields] OR
43. Flaifel A, Guzzetta M, Occidental M, et al. Testicular changes as“sars cov 2” [All Fields] OR “coronavirus disease 2019” [All Fields]
sociated with severe acute respiratory syndrome coronavirus 2
OR
“covid19”
Fields]
19” [All Fields])
AND (“semen”
(SARSCoV-2).[All
Arch
PatholOR
Lab“covid
Med. 2021;145(1):89. https://doi.
[All
Fields]
OR
“sperm”
[All
Fields]
OR
“testis”
[All
Fields]
OR “testes”
org/10.5858/arpa.2020- 0487-LE
44. [All
Rastrelli
G,
Di
Stasi
V,
Inglese
F,
et
al.
Low
testosterone
levels
pre- OR
Fields] OR “testicular” [All Fields] OR “epididymis” [All Fields]
dict clinical adverse outcomes in SARS-CoV-2 pneumonia patients.
“spermatic fluid” [All Fields] OR “seminal fluid” [All Fields] OR “prosAndrology. 2021;9(1):88-98. https://doi.org/10.1111/andr.12821
tatic secretion” [All Fields] OR “prostatic fluid” [All Fields] OR “male
45. Ma L, Xie W, Li D, et al. Effect of SARS-CoV-2 infecreproductive
Fields]function:
OR “maleAgenital
[Allbased
Fields]).
tion upon tract”
male [All
gonadal
singletract”
centerstudy.
medRxiv.
2020:2020.03.21.20037267.
https://doi.
Searches in Ovid Embase used the following terms: (‘2019 ncov’ OR
org10.1101/2020.03.21.20037267
‘sars
cov 2’ OR ‘covid-19’ OR covid19) AND (semen OR sperm OR
46. Pal R, Banerjee M. COVID-19 and the endocrine system: exploring
testis
OR testes OR testicular OR epididymis OR ‘spermatic fluid’ OR
the unexplored. J Endocrinol Invest. 2020;43(7):1027-1031. https://
‘seminal
fluid’ OR ‘prostatic
secretion’
doi.org/10.1007/s4061
8- 02001276-8 OR ‘prostatic fluid’ OR ‘male
47. reproductive
Okcelik S. COVID19
pneumonia
causes
lower testosterone levtract’ OR ‘male genital
tract’).
els. Andrologia. 2021;53(1): e13909. https://doi.org/10.1111/
and.13909
48. Kadihasanoglu M, Aktas S, Yardimci E, Aral H, Kadioglu A. SARS3CoV-| 2 Rpneumonia
E S U LT Saffects
A N Dmale
D I Sreproductive
C U S S I O Nhormone levels: a prospective, cohort study. The Journal of Sexual Medicine.
2021;18(2):256-264. https://doi.org/10.1016/j.jsxm.2020.11.007
After
reviewing the studies retrieved from the database, citations
49. Isidori AM, Buvat J, Corona G, et al. A critical analysis of the role of
and references were added based on a review of the title or abstract
testosterone in erectile function: from pathophysiology to treat(Figure
Fourteen
studies
and were
in this
ment-a1).
systematic
review.
Eurwere
Urol. eligible
2014;65(1):99112.included
https://doi.
org/10.1016/j.eururo.2013.08.048
study,
with 12 studies detecting SARS-CoV-2 in the male reproduc50. tive
Sansone
F, Gianfrilli
D, Lenzi
A. Endocrineonevaluation
tract,A,3Romanelli
determining
the impact
of COVID-19
sperm qualof erectile dysfunction. Endocrine. 2014;46(3):423- 430. https://doi.
ity and 3 exploring pathological changes in the testes of COVID-19
org/10.1007/s12020- 014- 0254-6
51. patients.
Mohamad NV, Wong SK, Wan Hasan WN, et al. The relationship between circulating testosterone and inflammatory cytokines in men.
Aging Male. 2019;22(2):129-140. https://doi.org/10.1080/13685
538.2018.1482487
3.1 | Detection of COVID-19 in the male
52. Nakazawa D, Ishizu A. Immunothrombosis in severe COVID-19.
reproductive
EBioMedicine. tract
2020;59:102942.
https://doi.org/10.1016/j.
ebiom.2020.102942
53. Twelve
Varga Z,
Flammer
AJ, Steigerthe
P, et
al. Endothelial
cell infection
andmale
studies
investigated
presence
of SARS-CoV-2
in the
endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-1418.
reproductive tract (eg semen, prostatic secretion or testicular tishttps://doi.org/10.1016/S0140 -6736(20)30937-5
are shown
in TableM,1.etMost
studies
were cross-sectional
54. sue)
Yafi and
FA, Jenkins
L, Albersen
al. Erectile
dysfunction.
Nature
Primers. 2016;2(1):
16003.subjects.
https://doi.org/10.1038/
inReviews
designDisease
and included
mainly Chinese
In brief, ten of 12
nrdp.2016.3
studies
reported that none of the participants had SARS-CoV-2 RNA
|
|
SANSONE
SANSONE Et
et Al
al..
2
55. Maiorino MI, Bellastella G, Giugliano D, Esposito K. From inflammation to sexual dysfunctions: a journey through diabetes, obesity,
and metabolic syndrome. J Endocrinol Invest. 2018;41(11):12491258. https://doi.org/10.1007/s40618- 018- 0872-6
56. Khalil A, Naneishvili T, Prasad N, Glancy J. SARS-CoV-2 myocarditis: what physicians need to know. BMJ Evid Based Med. 2021;
Jan 5 2021. [Epub ahead of print]. https://doi.org/10.1136/bmjeb
m-2020-111527
57. Magadum A, Kishore R. Cardiovascular manifestations of COVID-19
infection. Cells. 2020;9(11):2508. https://doi.org/10.3390/cells
9112508
58. Spagnolo P, Balestro E, Aliberti S, et al. Pulmonary fibrosis secondary to COVID-19: a call to arms? Lancet Respir Med. 2020;8(8):750752. https://doi.org/10.1016/S2213-2600(20)30222-8
59. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and
COVID-19: the potential role for antifibrotic therapy. Lancet
Respir Med. 2020;8(8):807-815. https://doi.org/10.1016/S2213
-2600(20)30225-3
60. Graney BA, Wamboldt FS, Baird S, et al. Looking ahead and behind at supplemental oxygen: a qualitative study of patients with
pulmonary fibrosis. Heart Lung. 2017;46(5):387-393. https://doi.
org/10.1016/j.hrtlng.2017.07.001
61. Cavezzi A, Troiani E, Corrao S. Hemoglobin, iron, and hypoxia
beyond inflammation. A narrative review. Clinics and Practice.
2020;10(2):24-30. https://doi.org/10.4081/cp.2020.1271
62. Eshraghi AA, Mirsaeidi M, Davies C, Telischi FF, Chaudhari N,
Mittal R. Potential mechanisms for COVID-19 induced anosmia and
dysgeusia. Front Physiol. 2020;11:1039. https://doi.org/10.3389/
fphys.2020.01039
63. Han AY, Mukdad L, Long JL, Lopez IA. Anosmia in COVID-19: mechanisms and significance. Chem Senses. 2020;45(6):423- 428. https://
doi.org/10.1093/chemse/bjaa040
64. Ottaviano G, Zuccarello D, Frasson G, et al. Olfactory sensitivity
and sexual desire in young adult and elderly men: an introductory
investigation. Am J Rhinol Allergy. 2013;27(3):157-161. https://doi.
org/10.2500/ajra.2013.27.3879
65. Siegel JK, Kung SY, Wroblewski KE, Kern DW, McClintock MK,
Pinto JM. Olfaction is associated with sexual motivation and satisfaction in older men and women. J Sex Med. 2021;18(2):295-302.
https://doi.org/10.1016/j.jsxm.2020.12.002
66. Schafer L, Mehler L, Hahner A, Walliczek U, Hummel T, Croy I. Sexual
desire after olfactory loss: quantitative and qualitative reports
of patients with smell disorders. Physiol Behav. 2019;201:64-69.
I NTRO D U C TI O N eh.2018.12.020
https://doi.org/10.1016/j.physb
67. Bendas J, Hummel T, Croy I. Olfactory function relates to sexual experience
in adults.
Arch Sex Behav.
2018;47(5):13331339.caused
https://
Since the
first case
of coronavirus
disease
2019 (COVID-19),
doi.org/10.1007/s1050 8- 018-1203-x
by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
68. Jannini EA, Lenzi A, Isidori A, Fabbri A. Subclinical erecwas reported
in Wuhan,proposal
China, itforhasa rapidly
spread andcategory
affectedin
tile dysfunction:
novel taxonomic
more than
million people
as of 17 794.
August
2020.1
sexual21medicine.
J Sex worldwide
Med. 2006;3(5):787https://doi.
org/10.1111/j.17436109.2006.00287.x enzyme II (ACE2) to
SARS-CoV-2
uses angiotensin-converting
69. Colonnello E, Ciocca G, Limoncin E, Sansone A, Jannini EA.
enter host cells, similar to SARS-CoV, which emerged 18 years ago. 2
Redefining a sexual medicine paradigm: subclinical premature ejacCOVID-19
induces respiratory-predominant multiorgan dysfunculation as a new taxonomic entity. Nat Rev Urol. 2021;18(2):115tion, including
myocardial, renal, enteric
and 00417
hepatic
127. https://doi.org/10.1038/s4158
5- 020-1 dysfunction,
3
70. Sansone
Limoncin
E, Colonnello
E, et al.
reduction
in sexMeanwhile,
which
coincidesA,with
the tissue
expression
of Harm
ACE2.
ual medicine. Sex Med Rev. 2021. [Epub ahead of print] https://doi.
several studies have shown that ACE2 is expressed in human testes
org/10.1016/j.sxmr.2021.01.005
(eg
spermatogonia, Leydig cells and Sertoli cells),4,5 suggesting that
71. Shamloul R, Ghanem H. Erectile dysfunction. Lancet.
the testes
may be another 165.
organ affected
by COVID-19.
2013;381(9861):153https://doi.org/10.1016/S0140
-6736
(12)60520
-0
Numerous
viruses
have been detected in human semen.6 Viruses
72. Foresta C, Caretta N, Corona G, et al. Clinical and metabolic
may
persist in semen and last longer in seminal fluid than in other body
evaluation of subjects with erectile dysfunction: a review with a
fluids due to the immune privilege of the testes and the contribution of
proposal flowchart. Int J Androl. 2009;32(3):198-211. https://doi.
the blood-testes
barrier to2605.2008.00932.x
resistance to therapeutic agents.7,8 Semen
org/10.1111/j.136573.also
Mulhall
JP, Giraldi
et as
al.Zika
Thevirus,
2018than
revision
to9,10
the
may
have higher
loadsA,ofHackett
viruses, G,
such
blood.
process
of care
model
evaluation
of erectile
Therefore,
the testes
may
act asfor
a reservoir
of virus,
which dysfunction.
may cause
J Sex Med. 2018;15(9):1280-1292. https://doi.org/10.1016/j.
imprecise evaluation of viral clearance in patients. Viruses, including
jsxm.2018.06.005
Zika
Ebola
cytomegalovirus
and
74.virus,
Corona
G,virus,
Sansone
A, Pallotti F, et
al.human
Peopleimmunodeficiency
smoke for nicotine,
but lose
sexual
reproductive
health
forcan
tar:be
a narrative
review
virus (HIV),
have
beenand
isolated
from semen
and
sexually transon
the
effect
of
cigarette
smoking
on
male
sexuality
and
reproduc6,11,12
Furthermore, some viruses (eg HIV, Zika virus, herpes
mitted.
tion. Journal of Endocrinol Investig. 2020;43(10):1391-1408. https://
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and that shows similar clinical presentations to COVID-19,18 could
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
research focusing on the effects of COVID-19 on male reproduc-
3.1 |
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