The Aging Male

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Impact of COVID 19 on erectile function

D. H. Adeyemi, A. F. Odetayo, M. A. Hamed & R. E. Akhigbe

To cite this article: D. H. Adeyemi, A. F. Odetayo, M. A. Hamed & R. E. Akhigbe

(2022) Impact of COVID 19 on erectile function, The Aging Male, 25:1, 202-216, DOI:
10.1080/13685538.2022.2104833

To link to this article: https://doi.org/10.1080/13685538.2022.2104833

© 2022 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group

Published online: 04 Aug 2022.

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THE AGING MALE
2022, VOL. 25, NO. 1, 202–216
https://doi.org/10.1080/13685538.2022.2104833

REVIEW ARTICLE

Impact of COVID 19 on erectile function

D. H. Adeyemia, A. F. Odetayob,c, M. A. Hamedc,d,e and R. E. Akhigbec,f
a
Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Osun State University, Nigeria;
b
Department of Physiology, University of Ilorin, Ilorin, Nigeria; cReproductive Biology and Toxicology Research Laboratory, Oasis of
Grace Hospital, Osogbo, Nigeria; dThe Brainwill Laboratories, Osogbo, Nigeria; eDepartment of Medical Laboratory Sciences, College
of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Nigeria; fDepartment of Physiology, Ladoke Akintola University of
Technology, Ogbomoso, Nigeria

ABSTRACT ARTICLE HISTORY

Purpose: COVID-19, a novel infection, presented with several complications, including socioeco­ Received 16 June 2022
nomical and reproductive health challenges such as erectile dysfunction (ED). The present Revised 18 July 2022
review summarizes the available shreds of evidence on the impact of COVID-19 on ED. Accepted 19 July 2022
Materials and methods: All published peer-reviewed articles from the onset of the COVID-19 Published online 5 August
2022
outbreak to date, relating to ED, were reviewed.
Results: Available pieces of evidence that ED is a consequence of COVID-19 are convincing. KEYWORDS
COVID-19 and ED share common risk factors such as disruption of vascular integrity, cardiovas­ Coronavirus; SARS-CoV-2;
cular disease (CVD), cytokine storm, diabetes, obesity, and chronic kidney disease (CKD). COVID- COVID-19; endothelial
19 also induces impaired pulmonary haemodynamics, increased ang II, testicular damage and dysfunction; erectile
low serum testosterone, and reduced arginine-dependent NO bioavailability that promotes dysfunction; testosterone
reactive oxygen species (ROS) generation and endothelial dysfunction, resulting in ED. In add­
ition, COVID-19 triggers psychological/mental stress and suppresses testosterone-dependent
dopamine concentration, which contributes to incident ED.
Conclusions: In conclusion, COVID-19 exerts a detrimental effect on male reproductive function,
including erectile function. This involves a cascade of events from multiple pathways. As the
pandemic dwindles, identifying the long-term effects of COVID-19-induced ED, and proffering
adequate and effective measures in militating against COVID-19-induced ED remains pertinent.

Introduction inflammatory response with attendant sperm damage

The outbreak of COVID 19 in the tail of 2019 ushered
in an unprecedented challenge for healthcare, with
reproductive health consequences [1]. Since the out­
break of the severe acute respiratory syndrome cor­
onavirus 2 (SARS-CoV-2)-caused infection in Wuhan,
China in December 2019, it has rapidly spread across
the globe to become a pandemic with negative
effects on socio-economic activities, posing a public
health challenge due to its associated high mortality
rate [2,3].
Although the lungs are the primary target organs
[4], the male reproductive tract is affected [5,6] either
directly or indirectly via endothelial dysfunction and
psychological imbalance. Studies have reported the
presence of the SARS-CoV-2 virus in the semen [7].
This virus may bind with angiotensin-converting
enzyme (ACE) 2 receptor (ACE2), to induce a hyper-
[5]. Studies have also shown that SARS-CoV-2 signifi­
cantly suppresses circulating testosterone, resulting in
impaired male fertility [8].
Notably, the SARS-CoV-2 virus does not only alter
testicular functions viz. testosterone concentration,
spermatogenesis, and sperm quality, it has also been
reported to alter male sexual and erectile function.
COVID-19 pandemic has been reported to distort the
sexual relationships between partners and sexual func­
tion [9–11]. It has also been demonstrated to cause
endothelial dysfunction, leading to impaired erectile
function [12–14]. Available data in the literature also
implicate COVID-19 in the aetiopathogenesis of pri­
mary organic or psychogenic erectile dysfunction (ED)
[15–17]. Hence, COVID-19-induced ED may involve
multiple pathways and the management may require
integrated multidisciplinary measures. Since the

CONTACT R. E. Akhigbe akhigberoland@gmail.com Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo,
Osun State, Nigeria; Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
� 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

infectious viral disease is novel and rapidly evolving,
this review provides detailed mechanistic pathways in
the pathogenesis of COVID-19-induced ED and an in-
depth evidence-based integrated, and multidisciplinary
approach to its management.
Structure of coronavirus
Coronavirus is a member of the Coronavirinae
subfamily that belongs to the Coronaviridae family of
the order Nidovirales. Four genera are enclosed in
the four family: Alphacoronavirus, Betacoronavirus,
Gammacoronavirus, and Deltacoronavirus [18]. SARS-
CoV-2, a representative of the Coronavirus family, has
a genome size of approximately 29.9 kb [19]. Four ana­
tomical proteins are enclosed in the coronavirus enve­
lope and they consist of spike-shaped glycoproteins
(S), envelope proteins (E), membrane proteins (M), and
nucleocapsid (N) [20]. The protein aids in the fastening
and initiation of the virus into the host cell [21].
The spike of the coronavirus is considered as a class
I viral membrane fusion protein representative that
likewise consists of those from influenza virus, Human
Immunodeficiency Virus (HIV), and Ebola virus [22].
The SARS-CoV-2 spike protein is again needed as
access to the host cell. The receptor-binding domain
(RBD) is enclosed in the S1 spike subunit. The host
and viral membrane fusion of the S2 protein spike
subunit serve as the entering site for the virus
(Bahman and Majid, 2022). The ACE2 receptor is used
by the SARS-CoV-2 virus to attach to the host cell that
consists of an array of respiratory epithelial cells,
alveolar macrophages, and monocytes [23,24].
Coronaviruses are the biggest among the RNA
viruses with a positive-sense single-stranded RNA
(þssRNA) in the range of 26–32 kb in length. They are
non-segmented enveloped viruses [25]. They possess a
50 -cap design and 30 -poly-A rear [26] The polyprotein
1a/1b (pp1a/pp1ab) encodes non-structural proteins
(NSPs) to model the replication-transcription complex
(RTC) in double-membrane vesicles (DMVS); it is pre­
cisely converted by the genomic RNA, which serves as
a template [27]. Transcription completion and succes­
sive recovery of leader RNA occur at transcription
regulatory progressions, positioned between open
reading frames (ORFs). These minus-strand sgRNAs
provide a guide for the creation of subgenomic
mRNAs [28,29],
Negative-stained SAR-CoV-2 particles examined in
an electron microscope brought to light the spherical
shape of SARS-CoV-2. The diameter ranges from 60 to
140 nm and an outlying superficial dotted with
THE AGING MALE 203
peculiar 9- to 12 nm-long spikes that accord virions
the manifestation of solar coronavirus [3].
Pathophysiology of coronavirus
COVID-19 evolves expressly over three noticeable
stages, which are the incubation stage, the symptom­
atic stage, and the pulmonary stage [30]. Viral intru­
sion is the first stride in COVID-19 pathogenesis
through its marked host cell receptor [31]. Three basic
glycoproteins (membrane, envelope, and nucleocap­
sid) are analytical for viral particle assembly and
release, and a fourth (Spike protein) is culpable for
adhesion and passage into the host cell [32–35].
Human ACE2 has been labeled by various research­
ers as a doorway receptor for SARS-CoV-2 [5,36–38].
Large respiratory droplets have been identified as the
most communicable means of SARS-CoV-2, undeviat­
ing infecting cells of the upper and lower respiratory
tract; the nasal ciliated and alveolar epithelial cells
before all else [39]. Though expressed in the lungs,
ACE2 is also expressed in other human tissues, such as
the kidney, heart, testis, small intestine, thyroid, and
adipose tissue (Akhigbe et al., 2020). The expression
hints at the possibility of the virus directly infecting
cells of other organ systems when viremia ensues [7].
SARS-CoV-2 has been made known to have a greater
affinity for the ACE2 receptor [40,41].
Viral and cell membranes fuse after the host cell
binding; this allows the virus to access the cell [31].
The binding of the host cell is not adequate to assist
the progress of membrane fusion, requiring S-protein
priming or gap by host cell proteases or transmem­
brane serine protease [42,43]. SARS-CoV-2, like other
coronaviruses, has been made known to possess a
furin-like cleavage site in the S-protein domain, situ­
ated between the S1 and S2 subunits [44]. Furine-like
proteases are universally expressed, notwithstanding
at lesser levels, signifying that S-protein priming at
this cleavage site may bequeath to the widened cell
tropism and improved transmissibility of SARS-CoV-
2 [31].
Nevertheless, it is yet to be ascertained if furine-like
protease-mediated cleavage is imperative for SARS-
CoV-2 host entry [31]. Most alluring is the evidence
that SARS-CoV-2 has established an exclusive S1/S2
cleavage site in its S-protein, marked by a four-amino
acid inclusion, which appears to be missing in all
other coronaviruses [45]. This molecular imitation has
been comprehensible as a competent transformative
adjustment that some viruses have earned for profit­
eering the host cellular machinery [31]. The RNA
204 D. H. ADEYEMI ET AL.
genome is duplicated and rewritten into basic and
adjunct proteins as soon as the nucleocapsid is con­
veyed into the cytoplasm of the host cell. Vesicles
exhaustive of the freshly formed viral particles are
then conveyed to and bind with the plasma mem­
brane, discharging them to infect other host cells in
the same manner [32,46].
Nonetheless, the definite role of the numerous
small viral peptides is yet to be professed. There is a
need for more research to have a clear-cut knowledge
of the basic attributes of SARC-CoV-2 that determine
different pathogenic systems [47].
Mechanism of erectile function
The process that culminates in penile erection entails
a mix of several physiological conditions that border
on the input from both central and peripheral nervous
systems. Besides, there are a series of the interplay
between several biological mediators, vasoactive
agents, neurotransmitters, and endocrine agents to
achieve the optimal erection necessary for sexual
intercourse [48]. The central processing unit in
response to tactile, visual, and imaginative stimuli
enhances penile erection. In other words, the central
and peripheral control systems remain the two major
established pathways that regulate or control penile
erection. Stimulations of the peripheral tissues
involved in erection elicit the response that is con­
trolled by spinal and somatic activities. In addition,
evidence from animal studies has suggested that the
central control of sexual arousal or erection is predom­
inantly localized in the limbic system structures. The
medial preoptic area, paraventricular nucleus, medial
amygdala, nucleus acumens, ventral tegmental area,
and hippocampus are primary structures in the regula­
tion of male sexual response [49]. Subsequently, a spi­
nal network consisting of primary afferent signals
emanating from the genitals, spinal interneurons, sym­
pathetic, parasympathetic, and somatic nuclei are
responsible for integrating signals from the periphery
thus eliciting reflexive erections [50].
In all of these, the roles of androgens in the regula­
tion of penile erection cannot be overemphasized as
androgens alongside some other molecular mediators
play significant roles in achieving an erection. There is
increasing evidence in the literature on the roles of
androgen in erectile functions. Studies have shown
that increased testosterone levels enhance sexual urge
and function by increasing the frequency of spontan­
eous erections, improving muscle mass, increasing
lean body mass, and reducing fat accumulation [51].
Morales et al. [52] reported that sexual dysfunction is
considered one of the major signals to determine low
testosterone levels in the body. For instance, lack of or
reduction in circulating testosterone levels may reduce
or abolish the effects of other transmitters or media­
tors involved in erection. It has been established that
dopamine, nitric oxide, oxytocin, and some other exci­
tatory amino acids enhance penile erection in mam­
mals [53].
Nitric oxide is considered one of the mediators of
penile erection [54] as the increase and subsequent
release of NO enhances smooth muscle relaxation and
stimulates blood flow to the erectile tissues, thereby
promoting penile erection [54]. During an erection,
the trabecular smooth muscle relaxes and vasodilata­
tion of the arteries leads to increased blood flow that
expands the sinusoidal spaces and lengthens and
enlarges the penis, resulting in the compression of the
subtunical venular plexus against the tunica albuginea.
Therefore, stretching of the tunica compresses the
emissary veins, hence reducing the outflow of blood
to a minimum. On the other hand, in a flaccid state,
inflow through the constricted and tortuous helicine
arteries is minimal, and there is free outflow via the
subtunical venular plexus. It is well established that
penile erection can be initiated with a single episode
of pelvic nerve stimulation, while maintenance of such
erection can be achieved through arterioles vasodilata­
tion and sustained blood flow to the corporeal body.
Ordinarily, sexual stimulation results in nitric oxide
(NO) release by non-adrenergic, non-cholinergic
(NANC) nerve ending in the corpus cavernosum and
the endothelial cells. NO then stimulates the cytosolic
enzymes guanylase cyclase to produce cGMP, which
reduces the smooth muscles of the corpus caverno­
sum with the consequent increase in blood flow into
the trabecular spaces and finally to an erection.
COVID 19 and erectile dysfunction: common
risk factors
COVID-19 and ED have been shown to share common
risk factors such as disruption of vascular integrity, car­
diovascular disease (CVD), cytokine storm, diabetes,
obesity, and chronic kidney disease (CKD) [55]. CVD
has been implicated with other comorbidities that pre­
dispose patients to more frequent and severe forms of
infections [56]. Studies have revealed that CVD and its
predisposing factors were positively correlated with
fatal outcomes in COVID-19 patients of all ages
[57,58]. This may be linked to the exacerbation of
cytokine storm-induced organ damage, a consequence

of pre-existing organ damage due to comorbid CVD
[59–61]. It is also likely that medications such as ACE-
inhibitors (ACEi) and angiotensin receptor blockers
(ARB) that are used in the management of CVD
increase the susceptibility to SARS-CoV-2 infection.
ACE2 degrades angiotensin II to angiotensin 1-7, thus
dampening its vasoconstriction, sodium retention, and
fibrotic effects [62,63]. Interestingly, SARS-CoV-2 does
not only gain entry through ACE2 but also subse­
quently downregulates the expression of ACE2, thus
attenuating its protective activities. Although, ACEi
and ARB activate ACE2/angiotensin 1-7/Mas receptor
signaling that confers beneficial antioxidant, antihyper­
tensive, and vasodilatory effects; ACEi/ARB-induced
upregulation of ACE2 could promote SARS-CoV-2
infection [63]. CVD activates systemic inflammation,
which combines with the virus-induced immune
response to increase the inflammatory burden [64],
leading to a cytokine storm and activation of adrener­
gic response with consequent plaque disruption and
acute coronary syndrome [64]. CVD also triggers
ischaemia-reperfusion imbalance that worsens COVID-
19 infection [64]. Similarly, CVD has been established
as a risk factor for ED. Endothelial dysfunction seen in
CVD impairs the relaxation of the smooth muscle cells
lining the arterioles, thus preventing vasodilatation
and erection [65]. Also, some anti-hypertensive drugs
used in the management of CVD such as b-blockers
and thiazide diuretics induce sexual and erectile dys­
function [66,67]. Although their impacts on male
reproductive functions remain controversial, statins
have been shown to worsen erectile function [66,68],
and ACEi to induce ED [66,69].
Diabetes and obesity have also been reported to
be independent risk factors for COVID-19 infection
and ED. Patients with diabetes have upregulated ACE2
and dipeptidyl peptidase-4 (DPP4) expression. These
receptors do not only modulate glucoregulatory proc­
esses, but they also serve as receptors for SARS-CoV-2
[36] and MERS-CoV [70] respectively, thus facilitating
viral uptake and increasing the susceptibility to severe
infection [19,71]. Also, the metabolic derangement,
chronic inflammation, and impaired innate and adap­
tive immune responses associated with diabetes and
obesity increase the susceptibility of diabetic and
obese patients to COVID-19 infection [72–75]. It is also
likely that the altered microenvironment associated
with diabetes promotes the emergence of pathogenic
SARS-CoV-2 variants with the propensity of causing a
more severe illness [76,77]. Similarly, diabetes-/obesity-
induced ED involves multiple pathways. Dyslipidaemia
associated with diabetes and obesity induces arterial
THE AGING MALE 205
thickening, atherosclerosis, vascular damage, and
remodeling via oxidative stress-mediated signaling
[78,79], resulting in NO-dependent endothelial dys­
function, impaired penile perfusion, and vascular ED
[80,81]. Also, diabetes-induced ischaemic-injury causes
somatic and autonomic neuropathies and impairment
of sensory impulses from the penis to the reflexogenic
erectile centre [82], leading to altered parasympathetic
activity that is essential for the relaxation of the
smooth muscle of the corpus cavernosum [83] and
consequent ED. Additionally, diabetes-induced and
obesity-induced pro-inflammatory state [78,79,84,85]
does not only promote COVID-19 infection [74,75], it
decreases NO bioavailability and downregulates NO/
cyclic guanosine-30 ,50 -monophosphate (cGMP) signal­
ing, thus leading to impaired penile relaxation and ED
[80,86]. Diabetes-/obesity-induced suppression of cir­
culating testosterone [80,84,85,87,88] has also been
shown to impair erectile function [89,90].
Although the underlying mechanisms remain
unclear, CKD, defined as a decrease in renal function
evidenced by declined glomerular filtration rate (GFR)
or renal damage (even with normal GFR), such as
increased albuminuria, abnormal urine sediment, or
structural abnormalities persisting for >3 months, with
implications for health [91], has been reported to be
the most prevalent comorbidity conveying an
increased risk for severe COVID-19 and also conveys
the highest risk for severe COVID-19 [92]. The
increased risk of SAR-CoV-2 infection and poor prog­
nosis of the infectious viral disease in CKD may be
secondary to the associated increased risk of infection
due to advanced comorbidity, uremia-associated
immune dysfunction, and frequent distortions of the
natural skin barrier [93–95]. Besides modulating the
immune system, CKD-induced uremia also impairs the
hypothalamic-pituitary-testicular axis. Uremic serum
associated with CKD inhibits luteinizing hormone (LH)
signaling at the level of the Leydig cells [96], resulting
in low testosterone levels and impaired negative feed­
back on LH production [97]. CKD is also associated
with increased oestrogen and prolactin levels [97].
These impair libido and erectile function [98]. CKD has
also been shown to promote atherosclerotic vascular
disease [99], resulting in endothelial dysfunction,
impaired penile circulation, and ED [100,101]. CKD also
causes uremia-induced autonomic neuropathy
[102,103], which promotes ED [101]. Other causes of
ED in CKD include the use of medications like digoxin,
histamine antagonists, calcium channel blockers,
b-blockers, and methyldopa [66,101], depression and
antidepressant [66,101], erythropoietin-driven anaemia
206 D. H. ADEYEMI ET AL.
that results in reduced oxygen availability and NO
generation [104,105].
ED as a complication of COVID 19
COVID 19 and sexual behaviour
It would be expected that COVID-19- related restric­
tions and quarantine/ lockdown periods would pro­
mote sexual intimacy among couples/sexual partners;
surprisingly, it did not. In a correlational study by Cito
et al. [106], the number of sexual intercourses signifi­
cantly reduced during the quarantine period. Also,
there was a reduced masturbation activity among
those who reported autoerotism. The reduced sexual
activities were reported to be due to poor privacy and
lack of sexual desire. These findings are in consonance
with the reports of Eroglu et al. [107] that docu­
mented that the COVID-19 pandemic led to increased
anxiety levels in healthcare workers, which negatively
affected their sexual functions. This was associated
with a significant deterioration in erectile function,
orgasmic function, sexual desire, intercourse satisfac­
tion, and overall satisfaction as well as decreased fore­
play times and a change of intercourse positions to
less face-to-face [107–109]. In addition, Fang et al. [9]
observed that COVID-19 pandemic-induced decreased
sexual function was associated with increased anxiety
and depression and decreased frequency of sexual life.
Previous studies have shown that the fear of COVID-
19 may induce anxiety and panic, which may degener­
ate into negative psychological reactions, including
adjustment disorder and depression [110] that have
been directly associated with decreased sexual interest
[111–113]. Hence, the loss of sexual interest may be
due to, at least in part, generalized anxiety dis­
order [111,114].
It is interesting to note that although some studies
implicated COVID-19-led anxiety and depression with
reduced sexual activity during the pandemic, reduced
sexual activity may worsen anxiety and depression.
Mollaioli et al. [115] in a web-based case-control study
compared subjects who had sexual activity and those
who did not during the lockdown period. Their find­
ings revealed significantly reduced anxiety and depres­
sion scores in subjects who were sexually active
during the lockdown. They also reported that sexual
activity and living with/without a partner during the
lockdown were factors that influenced anxiety and
depression scores, thus demonstrating the protective
role of sexual activity toward psychological distress.
Therefore, the relationship between sexual activity and
psychological stability may be bi-directional.
In a report of three cases by Salama and Blgozah
[116], it was observed that COVID-19-infected men
developed a decline in sexual function and premature
ejaculation. This was associated with a further decline
during recovery, but normal levels of testosterone, LH,
FSH, oestradiol, and prolactin. On the contrary, Neto
et al. [117] observed an increased pornography con­
sumption and masturbatory frequency among the
studied population, although there was a marked
decline in libido and general sexual satisfaction. The
increased pornography consumption explains the
upsurge in the statistics reported by pornography
websites [118]. COVID-19-associated social distancing
and its attendant negative influence on physical, intel­
lectual, and emotional wellbeing may cause a rise in
pornography consumption and masturbatory activity
[119]. The increased length of time spent at home and
the anxiety generated by the pandemic might have
led to the rise in masturbatory frequency [120]. The
observed rise in masturbatory frequency might have
resulted in a reduced interest in real physical sexual
intimacy, poor libido, and ED [121,122]. Also, among
men who have sex with men, the use of sex phones,
webcams, and pornography consumption increased
but risky sexual behaviour and sexual repertoire
reduced during the pandemic [123]. However, no
study documented whether the masturbation
practices were solo masturbation, solo masturbation
with pornography consumption, or mutual partner
masturbation.
Interestingly, Zhang et al. [124] reported that the
COVID-19 pandemic did not significantly alter the fre­
quency of sexual intercourse, quality of sexual lives,
and emotional bonding. A study among male canna­
bis users revealed that the COVID-19 pandemic
increased sexual frequency and did not alter overall
sexual function [125]. Karagoz et al. [126] observed
lower sexual function and episodes of sexual inter­
course, and increased sexual avoidance and solitary
sexual approach behaviour (such as masturbation and
pornography consumption) during the pandemic
period compared to the pre-pandemic period,
although the couples that spent more time together
during the pandemic reported better sexual function.
Although the impact of COVID-19 infection on sex­
ual functions is yet to be fully explored, it has been
reported that the impaired pulmonary hemodynamics,
endothelial dysfunction, and testicular damage elicited
by the virus may cause ED [4]. Suppression of the
hypothalamic-pituitary-adrenocortical axis [127], direct
inhibition of the spinal erection center from the ner­
vous system, excessive sympathetic outflow or

increased circulating catecholamines [128], and the
modulation of a short allele in the promoter region of
the serotonin transporter (5-HTTLPR) gene [129–132]
may also play key roles.
COVID 19 and testosterone
Testosterone, a key player in male reproductive func­
tion, has also been established to play an immunomo­
dulatory role [133]. Testosterone enhances endothelial
function and facilitates relaxation of the corpora caver­
nosa, increases libido and energy, and suppresses
depressive symptoms [134–136]. It also modulates the
expression of inflammatory mediators. However, tes­
tosterone seems to exert dimorphism in inflammation
regulation. In a cohort of women with SARS-CoV-2
infection, Di Stasis et al. [137] observed that a higher
testosterone level was associated with greater severity
of the infection evidenced by higher circulating levels
of pro-inflammatory markers and longer stay in the
intensive care unit. Although there is a paucity of evi­
dence in females, studies have demonstrated that an
increased testosterone level in women with Polycystic
Ovarian Syndrome (PCOS) is associated with a rise in
pro-inflammatory markers [138,139]. This is an abso­
lute contrast to the findings in male cohorts with
SARS-CoV-2 infection that revealed that a lower testos­
terone level was associated with greater severity of
SARS-CoV-2 infection [140–143]. The finding in males
is in agreement with the anti-inflammatory activity of
testosterone. Testosterone inhibits inflammation by
upregulating anti-inflammatory cytokines and sup­
pressing pro-inflammatory cytokines [144].
Testosterone downregulates IL-6 gene expression
[145] and also exerts an inhibitory effect on TNF-a
production by macrophages [146]. Conversely, IL-6
and TNF-a suppress circulating testosterone via
impairment of the hypothalamic-pituitary-testicular
axis [147,148] and suppression of Leydig cell function
[149,150]. An optimal testosterone level alleviates
inflammation with better outcomes, while a low tes­
tosterone level promotes the inflammatory response.
Chen et al. [23] reported a decline in circulating tes­
tosterone and ACE2 expression in SARS-CoV-2 infec­
tion, which correlated with the severity of COVID-19
infection [151]. This is in agreement with the findings
of other studies that observed a low concentration of
testosterone in SARS-CoV-2 infection [17,140]. SARS-
CoV-2-induced low circulating testosterone may be
dependent on the expression of ACE2 by the Leydig
cells. SARS-CoV-2 likely gains entry into the testis via
ACE2 in the Leydig cells replicates and activates p38
THE AGING MALE 207
mitogen-activated protein kinases (MAPK) and extra­
cellular-regulated protein kinases (ERK), leading to
hyper-inflammatory response [5,6,152] and oxido-
inflammatory damage to the testis with resultant
reduced testosterone production [6]. The reduced tes­
tosterone levels may also be due to COVID-19-induced
hypercoagulation-mediated ischaemia at the micro­
vascular level, leading to testicular injury [153] and
impaired testosterone production. The observed low
testosterone levels in COVID-19 infected patients
modulate endothelial function [135], via oxidative
stress-dependent signaling (involving pro-inflamma­
tory cytokines) and results in ED [144,154].
Testosterone has also been reported to enhance
dopamine release and NO synthesis [65]. Hence, SARS-
CoV-2-induced repression of circulating testosterone
suppresses the synthesis and release of dopamine
[155], leading to impaired sexual motivation, copula­
tory efficiency, and erectile function. Additionally, the
reduced dopamine reduces NO synthase (NOS) in the
cell bodies of the paraventricular nucleus and impairs
urogenital reflexes and penile erection [156,157], lead­
ing to ED.
COVID 19 and ACE
Converging lines of evidence have shown that the
virus adversely affects the endothelium and endothe­
lial layers across tissues in the body [158] and this
might suggest the relationship between the virus and
one of the protein substrates produced by the endo­
thelium, angiotensin-converting enzyme 2 (ACE2) [18].
Zhang et al. [71] reported that the virus accessed
most host cells through the protein ACE2. Endothelial
dysfunction is considered one of the major symptoms
of determining COVID-19 presence in the body [159].
The role of the Renin-Angiotensin-System (RAS) in the
pathophysiology of several vascular diseases including
erectile dysfunction has been previously established
[160]. Ordinarily, the renin-angiotensin system oper­
ates by converting precursor angiotensinogen to an
inactive decapeptide called Angiotensin-1 (Ang 1),
which is mediated by renin bioavailability. This
inactive enzyme Ang 1 is further converted to its
active form, Ang II, through an enzyme present in the
lungs known as Angiotensin Converting Enzymes
(ACE). ACE2, which acts as a counterbalance to ACE,
cleaves phenylalanine from Ang II and hydrolyzes it to
angiotensin 1-7 (11). SAR-CoV-2 binding overwhelms
ACE2, leading to a rise in Ang II (that cannot be con­
verted to angiotensin 1-7 due to unavailability of
ACE2) [5], which in turn enhances tyrosine
208 D. H. ADEYEMI ET AL.
phosphorylation of endothelial NOS (eNOS) via an AT1
receptor-, H2O2-, and proline-rich tyrosine kinase 2
(PYK2)-dependent mechanism, resulting in attenuation
of NO production, impaired endothelium-dependent
vasodilatation, endothelial dysfunction [161], and ED.
In addition, Ang II may impair vascular tone by upre­
gulation of superoxide-mediated impairment of endo­
thelial function [162], leading to reduced penile
perfusion and ED. Angiotensin II, via angiotensin II
type 1 receptor (AT1 receptor) [163], causes vascular
constriction, endothelial cell migration, proliferation,
and hypertrophy and increases uptake and oxidation
of LDL by endothelial cells as well as oxyradical pro­
duction, thus leading to endothelial dysfunction
[78,164] and resultant ED.
ACE2/Ang 1-7/Mas receptor signaling has been
reported to play a role in testosterone biosynthesis
and spermatogenesis [165,166]. ACE2 is the primary
source of Ang (1-7) via the hydrolysis of Ang II [167]
or Ang I to Ang (1-9) [168,169], with subsequent gen­
eration of Ang (1-7) through ACE and neutral endo­
peptidase hydrolysis [170]. Angiotensins regulate
testosterone production via Leydig cell inhibition by
Ang II [166]. Hence, COVID-19-led downregulation of
ACE2 upregulates Ang II, which in turn reduces the
activation of the upstream angiotensin-mediated path­
way and inhibits Leydig cell function. This suppresses
testosterone production and promotes ED.
COVID 19 and arginine
The T-cell function of the immune system has been
shown to depend on the circulating arginine [171].
Suppression of the circulating arginine has been impli­
cated in the reduction in lymphocytes’ capacity to
increase rapidly in number [172]. Arginine deficiency
has also been shown to reduce the proliferating cap­
acity of T-cells [173]. In vitro studies have demon­
strated that arginine can help to restore T-cell
function [174]. Arginine depletion inhibits T-cell recep­
tor signaling, which may result in T-cell dysfunction,
and increases reactive oxygen species (ROS) produc­
tion, thus aggravating inflammation [175,176]. Ochoa
et al. [177] implicated a decrease in arginine bioavail­
ability in reduced T-cell response and function, with
consequent increased susceptibility to infections.
Reizine et al. [178] revealed that the proliferative abil­
ity of T-cells was significantly reduced in patients with
COVID-19 but was restored following arginine supple­
mentation. In another study by Fiorentino et al. [179],
it was observed that patients treated with arginine
were discharged earlier with little respiratory support
when compared with patients in the placebo arm.
Since chronic inflammation persistence is fundamental
in COVID-19 disease, arginine supplementation could
be beneficial in controlling COVID-19 [180–183].
Hence, a low level of arginine may increase an individ­
ual’s susceptibility to COVID-19 infection.
In an attempt to study the effect of COVID-19 on
arginine concentration, the level of arginine was com­
pared between healthy adults with no symptoms of
COVID-19, and symptomatic adults that were hospital­
ized for COVID-19, and symptomatic children that
were hospitalized for COVID-19 [184]. It was observed
that the hospitalized adults and children showed sig­
nificantly reduced bioavailability and level of plasma
arginine when compared with the controls [184]. This
is in agreement with another study that observed an
inverse relationship between the plasma level of argin­
ine and the severity of COVID-19 [185]. Therefore, a
low level of arginine may predispose an individual to
COVID-19 and also worsen its progression with likely
complications, including reproductive health
challenges.
Erection is an enlarged and rigid state of the penis
in which one of the main regulators is nitric oxide
(NO) [186]. L-arginine is the natural precursor for the
synthesis of NO and its availability at the physiologic
level is believed to have a positive effect on the pro­
duction of NO [187]. Hence, reduced NO bioavailability
that may be a consequence of a marked reduction in
L-arginine has been implicated as a major cause of
erectile dysfunction. In the presence of nitric oxide
synthase isoforms, L-arginine is converted to NO to be
released from both the cavernosal nerve ending and
the endothelial cells of the artery that supplies the
penis (penile artery) following the stimulation from
the spinal cord [188]. Once the NO has been released,
it will lead to a cascade of events that will eventually
lead to the relaxation in the smooth muscle of the
corpora cavernosa, veno-occlusion, and penile erection
[186]. Hence, reduced arginine-dependent NO bioavail­
ability may contribute to COVID-19-induced ED. This
may involve several pathways. Reduced NO bioavail­
ability may downregulate NO/cGMP signaling, leading
to impaired relaxation of the corpus carvenosa and ED
[80,86]. Also, a low level of arginine-dependent NO
inhibits the vasodilator activity of NO and blood flow
[78], thus impairing penile perfusion and erection.
Furthermore, since arginine has been demonstrated to
exert antioxidant and anti-inflammatory effects [189], a
low level of arginine impairs its capacity to scavenge
Ang II-induced free radical generation, leading to
endothelial dysfunction [162], and ED.
 THE AGING MALE 209

Figure 1. Schematic illustration of the possible pathway of COVID-19-induced erectile dysfunction. SARS-CoV-2 impairs pulmonary
hemodynamics and arginine biosynthesis, leading to reduced circulating nitric oxide (NO) and erectile dysfunction (ED). SARS-CoV-
2 may also induce psychological stress and testicular injury, which results in suppressed testosterone and dopamine, leading to
ED. SARS-CoV-2-ACE2 binding may overwhelm ACE2 with resultant rise in angiotensin II (Ang II), which in turn promotes the gen­
eration of reactive oxygen species (ROS) that may induce oxidative stress and accumulation of pro-inflammatory cytokines, with
consequent endothelial dysfunction and ED.

COVID 19 and psychological/mental stress
COVID-19 preventive measures, which include social
isolation and distancing, as well as the fear of con­
tracting the deadly virus, financial insecurities, and
uncertainty about the future increased the psycho­
logical distress of people globally. This worsened
increased unemployment and homeschooling
[190–192]. This led to reduced sexual interaction,
forced separation of intimate partners, widening of
communication gap among some sexual partners, and
escalation of marital conflicts, resulting in reduced sex­
ual activities and increased sexual dissatisfaction
[108,193,194]. The burden of lack of privacy due to
social confinement, distorted sexual desire, and
expression were also noted to intensify mental stress
and sexual dysfunction [195]. COVID-19-driven anxiety
and depression were observed to elicit male sexual
dysfunction, especially erectile function [9,196]. Likely,
the reduced erectile function observed during the
pandemic was not unrelated to the perceived adverse
circumstances and activation of peoples’ psychological
vulnerabilities in response to increased emotional dur­
ess [197]. It is also likely that libido and response to
erotic stimuli may be negatively altered by the per­
ceived threat or anticipated negative repercussions of
sex (as a potential risk factor for SARS-CoV-2
transmission) [198] and ineffective cognitive process­
ing of erotic stimuli due to cognitive distraction.
Management of ED amidst COVID 19 pandemic
COVID-19 pandemic came with some restrictive meas­
ures in an attempt to curtail the spread of the rapidly
spreading infection. The lockdown measure, including
stay-at-home orders, movement/travel restrictions, and
school closures considerably affected the utilization of
medicare and medication-seeking patterns [199–205].
Although data reporting healthcare utilization during
the pandemic is scarce, about 40.9% of US adults
were reported to avoid medical care during the
COVID-19 pandemic [199]. Also, following significant
community transmission of SARA-CoV-2 [199,203],
many elective surgeries for urological conditions like
ED were postponed [111,206–208]. The Canadian
Urological Association reported a massive deviation in
surgical patterns as only emergency and urgent cases
were attended to with the introduction of virtual care
for most other male sexual health cases [209]. This
likely took its toll on the management of ED, poten­
tially prolonging its evaluation and prompt manage­
ment and possibly worsening ED. Even where
medicare was obtainable, the increased
210 D. H. ADEYEMI ET AL.
unemployment and financial insecurities associated
with the COVID-19 pandemic likely exacerbated the
decision of patients to utilize healthcare.
Conclusion and future perspectives
Summing up, the present review showed emerging
shreds of evidence on the association between COVID-
19 and ED (Figure 1). Although COVID-19 and ED
share common risk factors such as disruption of vascu­
lar integrity, CVD, cytokine storm, diabetes, obesity,
and chronic kidney disease CKD; ED has been demon­
strated as a major complication of COVID-19. The
pathophysiology of COVID-19-induced ED may involve
several pathways. Impaired pulmonary haemodynam­
ics, increased Ang II, testicular damage and low circu­
lating testosterone, and reduced arginine-dependent
NO bioavailability associated with SARS-CoV-2 infec­
tion promote ROS generation and endothelial dysfunc­
tion, resulting in ED. COVID-19-driven psychological/
mental stress and reduced testosterone-dependent
dopamine concentration contribute to incident ED.
Author contributions
Category 1: (a) Conception and Design: Adeyemi DH,
Odetayo AF, Hamed MA, Akhigbe RE.
Category 2: (a) Drafting the Article: Adeyemi DH, Odetayo
AF, Hamed MA, Akhigbe RE; (b) Revising it for Intellectual
Content: Adeyemi DH, Odetayo AF, Hamed MA, Akhigbe RE.
Category 3: (a) Final Approval of the Completed Article:
Adeyemi DH, Odetayo AF, Hamed MA, Akhigbe RE.
Disclosure statement
No potential conflict of interest was reported
the author(s).
Funding
The author(s) reported there is no funding associated with
the work featured in this article.
ORCID
R. E. Akhigbe http://orcid.org/0000-0002-3874-5927
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