Impact of COVID 19 on erectile function

Abstract Purpose: COVID-19, a novel infection, presented with several complications, including socioeconomical and reproductive health challenges such as erectile dysfunction (ED). The present review summarizes the available shreds of evidence on the impact of COVID-19 on ED. Materials and methods: All published peer-reviewed articles from the onset of the COVID-19 outbreak to date, relating to ED, were reviewed. Results: Available pieces of evidence that ED is a consequence of COVID-19 are convincing. COVID-19 and ED share common risk factors such as disruption of vascular integrity, cardiovascular disease (CVD), cytokine storm, diabetes, obesity, and chronic kidney disease (CKD). COVID-19 also induces impaired pulmonary haemodynamics, increased ang II, testicular damage and low serum testosterone, and reduced arginine-dependent NO bioavailability that promotes reactive oxygen species (ROS) generation and endothelial dysfunction, resulting in ED. In addition, 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
The outbreak of COVID 19 in the tail of 2019 ushered in an unprecedented challenge for healthcare, with reproductive health consequences [1]. Since the outbreak of the severe acute respiratory syndrome coronavirus 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-inflammatory response with attendant sperm damage [5]. Studies have also shown that SARS-CoV-2 significantly 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 function [9][10][11]. It has also been demonstrated to cause endothelial dysfunction, leading to impaired erectile function [12][13][14]. Available data in the literature also implicate COVID-19 in the aetiopathogenesis of primary organic or psychogenic erectile dysfunction (ED) [15][16][17]. Hence, COVID-19-induced ED may involve multiple pathways and the management may require integrated multidisciplinary measures. Since the infectious viral disease is novel and rapidly evolving, this review provides detailed mechanistic pathways in the pathogenesis of COVID-19-induced ED and an indepth 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 anatomical proteins are enclosed in the coronavirus envelope 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 5 0 -cap design and 3 0 -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 precisely converted by the genomic RNA, which serves as a template [27]. Transcription completion and successive 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 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 symptomatic stage, and the pulmonary stage [30]. Viral intrusion is the first stride in COVID-19 pathogenesis through its marked host cell receptor [31]. Three basic glycoproteins (membrane, envelope, and nucleocapsid) are analytical for viral particle assembly and release, and a fourth (Spike protein) is culpable for adhesion and passage into the host cell [32][33][34][35].
Human ACE2 has been labeled by various researchers 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, undeviating 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 transmembrane 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, situated 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- 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 profiteering the host cellular machinery [31]. The RNA genome is duplicated and rewritten into basic and adjunct proteins as soon as the nucleocapsid is conveyed into the cytoplasm of the host cell. Vesicles exhaustive of the freshly formed viral particles are then conveyed to and bind with the plasma membrane, 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 controlled by spinal and somatic activities. In addition, evidence from animal studies has suggested that the central control of sexual arousal or erection is predominantly 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 regulation of male sexual response [49]. Subsequently, a spinal network consisting of primary afferent signals emanating from the genitals, spinal interneurons, sympathetic, 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 regulation 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 spontaneous 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 mediators involved in erection. It has been established that dopamine, nitric oxide, oxytocin, and some other excitatory amino acids enhance penile erection in mammals [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 vasodilatation 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 vasodilatation 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 cavernosum 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, cardiovascular disease (CVD), cytokine storm, diabetes, obesity, and chronic kidney disease (CKD) [55]. CVD has been implicated with other comorbidities that predispose 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][60][61]. It is also likely that medications such as ACEinhibitors (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 subsequently 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, antihypertensive, and vasodilatory effects; ACEi/ARB-induced upregulation of ACE2 could promote SARS-CoV-2 infection 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 processes, 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 adaptive immune responses associated with diabetes and obesity increase the susceptibility of diabetic and obese patients to COVID-19 infection [72][73][74][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-/obesityinduced ED involves multiple pathways. Dyslipidaemia associated with diabetes and obesity induces arterial 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 prognosis 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][94][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 feedback 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 that results in reduced oxygen availability and NO generation [104,105].

COVID 19 and sexual behaviour
It would be expected that COVID-19-related restrictions and quarantine/ lockdown periods would promote sexual intimacy among couples/sexual partners; surprisingly, it did not. In a correlational study by Cito et al. [106], the number of sexual intercourses significantly 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 documented 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 satisfaction, and overall satisfaction as well as decreased foreplay times and a change of intercourse positions to less face-to-face [107][108][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 degenerate into negative psychological reactions, including adjustment disorder and depression [110] that have been directly associated with decreased sexual interest [111][112][113]. Hence, the loss of sexual interest may be due to, at least in part, generalized anxiety disorder [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 findings revealed significantly reduced anxiety and depression 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 consumption 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, intellectual, 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 frequency of sexual intercourse, quality of sexual lives, and emotional bonding. A study among male cannabis 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 intercourse, 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 sexual 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 nervous 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][130][131][132] may also play key roles.

COVID 19 and testosterone
Testosterone, a key player in male reproductive function, has also been established to play an immunomodulatory role [133]. Testosterone enhances endothelial function and facilitates relaxation of the corpora cavernosa, increases libido and energy, and suppresses depressive symptoms [134][135][136]. It also modulates the expression of inflammatory mediators. However, testosterone 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 evidence 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 absolute contrast to the findings in male cohorts with SARS-CoV-2 infection that revealed that a lower testosterone level was associated with greater severity of SARS-CoV-2 infection [140][141][142][143]. The finding in males is in agreement with the anti-inflammatory activity of testosterone. Testosterone inhibits inflammation by upregulating anti-inflammatory cytokines and suppressing 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 testosterone level promotes the inflammatory response.
Chen et al.
[23] reported a decline in circulating testosterone and ACE2 expression in SARS-CoV-2 infection, 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 mitogen-activated protein kinases (MAPK) and extracellular-regulated protein kinases (ERK), leading to hyper-inflammatory response [5,6,152] and oxidoinflammatory damage to the testis with resultant reduced testosterone production [6]. The reduced testosterone levels may also be due to COVID-19-induced hypercoagulation-mediated ischaemia at the microvascular 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-inflammatory 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, copulatory 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], leading to ED.

COVID 19 and ACE
Converging lines of evidence have shown that the virus adversely affects the endothelium and endothelial 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 endothelium, 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 operates 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 converted to angiotensin 1-7 due to unavailability of ACE2) [5], which in turn enhances tyrosine phosphorylation of endothelial NOS (eNOS) via an AT1 receptor-, H 2 O 2 -, 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 upregulation of superoxide-mediated impairment of endothelial 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 production, 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 generation of Ang (1-7) through ACE and neutral endopeptidase 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 pathway 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 implicated in the reduction in lymphocytes' capacity to increase rapidly in number [172]. Arginine deficiency has also been shown to reduce the proliferating capacity of T-cells [173]. In vitro studies have demonstrated that arginine can help to restore T-cell function [174]. Arginine depletion inhibits T-cell receptor signaling, which may result in T-cell dysfunction, and increases reactive oxygen species (ROS) production, thus aggravating inflammation [175,176]. Ochoa et al. [177] implicated a decrease in arginine bioavailability in reduced T-cell response and function, with consequent increased susceptibility to infections. Reizine et al. [178] revealed that the proliferative ability of T-cells was significantly reduced in patients with COVID-19 but was restored following arginine supplementation. 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][181][182][183]. Hence, a low level of arginine may increase an individual's susceptibility to COVID-19 infection.
In an attempt to study the effect of COVID-19 on arginine concentration, the level of arginine was compared between healthy adults with no symptoms of COVID-19, and symptomatic adults that were hospitalized for COVID-19, and symptomatic children that were hospitalized for COVID-19 [184]. It was observed that the hospitalized adults and children showed significantly 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 arginine 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 production 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 bioavailability may contribute to COVID-19-induced ED. This may involve several pathways. Reduced NO bioavailability 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.

COVID 19 and psychological/mental stress
COVID-19 preventive measures, which include social isolation and distancing, as well as the fear of contracting the deadly virus, financial insecurities, and uncertainty about the future increased the psychological distress of people globally. This worsened increased unemployment and homeschooling [190][191][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 sexual 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 duress [197]. It is also likely that libido and response to erotic stimuli may be negatively altered by the perceived threat or anticipated negative repercussions of sex (as a potential risk factor for SARS-CoV-2 transmission) [198] and ineffective cognitive processing of erotic stimuli due to cognitive distraction.

Management of ED amidst COVID 19 pandemic
COVID-19 pandemic came with some restrictive measures 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][200][201][202][203][204][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][207][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, potentially prolonging its evaluation and prompt management and possibly worsening ED. Even where medicare was obtainable, the increased 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 vascular integrity, CVD, cytokine storm, diabetes, obesity, and chronic kidney disease CKD; ED has been demonstrated as a major complication of COVID-19. The pathophysiology of COVID-19-induced ED may involve several pathways. Impaired pulmonary haemodynamics, increased Ang II, testicular damage and low circulating testosterone, and reduced arginine-dependent NO bioavailability associated with SARS-CoV-2 infection promote ROS generation and endothelial dysfunction, resulting in ED. COVID-19-driven psychological/ mental stress and reduced testosterone-dependent dopamine concentration contribute to incident ED.

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Funding
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