key: cord-0773214-kp4j9snc authors: Sansone, Andrea; Mollaioli, Daniele; Ciocca, Giacomo; Colonnello, Elena; Limoncin, Erika; Balercia, Giancarlo; Jannini, Emmanuele A. title: “Mask up to keep it up”: Preliminary evidence of the association between erectile dysfunction and COVID‐19 date: 2021-03-30 journal: Andrology DOI: 10.1111/andr.13003 sha: acd27850a5df453a339e4324b76eabc1794dcde2 doc_id: 773214 cord_uid: kp4j9snc 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. COVID-19, the coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), features several clinical phenotypes, ranging from mild to severe forms: The "cytokine storm" 1,2 may lead to the development of microvascular thrombotic and inflammatory processes, which in turn promote progression to possibly lethal pulmonary complications. Some evidence has also suggested that even "silent" asymptomatic forms of COVID-19 could have subclinical microvascular involvement 3, 4 and that long-term cardiovascular sequelae could be expected in COVID-19 patients. 5, 6 Endothelial dysfunction has been considered as the potential trigger for the onset of more severe forms, as well as the link between different comorbidities associated with COVID-19 7 : Indeed, COVID-19 is by all means an endothelial disease, in which systemic manifestations of the disease can potentially be due to tissue ischemia resulting from alterations in endothelial thrombotic/fibrinolytic balance. 8 Additionally, endothelial cells express many of the co-factors used by the SARS-CoV-2 to invade host cells. 9 Erectile dysfunction (ED) has been often considered a hallmark of endothelial dysfunction, 10, 11 and as such, a potential association between ED and COVID-19 has also been postulated. 12 Another interesting take on the association between ED and COVID-19 comes from the shared risk factors for the two conditions. Indeed, severity and prevalence of both ED and COVID-19 are higher among men suffering from hypertension, obesity, diabetes, and history of cardiovascular disease. [13] [14] [15] [16] Broadly speaking, ED is often considered a clinical marker of a "dysfunctional" phenotype, which often features cardiovascular events at an early age. This would possibly suggest that subjects with ED, due to the underlying conditions which impair erectile response, could also be more susceptible to contracting COVID-19. The present study is, to our knowledge, the first one investigating the prevalence of ED and the possible association between ED and COVID-19 from real-life data in a large survey. In order to retrieve an adequate sample for the present study, we reviewed data from the Sex@COVID study, 17 a previous research project by our group. The Sex@COVID study was an anonymous web-based questionnaire investigating the psychological, relational, and sexual health of Italian subjects between April 7 and May 4, Overall, 6821 subjects aged 18 years or older (females, 4177; males, 2644; mean age 32.83 ± 11.24 years) living in Italy, stratified according to marital status and sexual activity during lockdown, participated in the Sex@COVID study. All subjects provided informed consent to the study, which has been approved by our local Ethical Committee. Nine hundred and eighty-five sexually active men were therefore identified in the Sex@COVID cohort, among which 25 (2.54%) reported being tested as positive for COVID-19. Anxiety and depression were, respectively, measured by the GAD-7 18 (Generalized Anxiety Disorder Scale) and the PHQ-9 19 (Patient Health Questionnaire), two questionnaires validated for clinical use, which have already been used to assess psychological outcomes of For each test, scores ≥10 are considered suggestive of general anxiety disorder and depressive disorder, respectively. Statistical analysis was performed with the statistical software R (version 3.6.2); statistical significance was set at p < 0.05. Propensity score matching was used in order to retrieve two matching samples, based on age, body mass index (BMI), and GAD-7 and PHQ-9 scores, using a 1:3 ratio to improve reliability of the results. Assessment of normality was performed using the Shapiro-Wilk test of normality. Wilcoxon rank sum test with continuity correction and Fisher's exact test (one-tailed) were used to assess differences in the numerical and categorical variables between study groups. Chi-squared goodness-of-fit test was used to measure differences in the prevalence of ED between study groups. Logistic regression models were fitted to assess to which extent age, GAD-7 and PHQ-9 scores, BMI, and history of COVID-19 affected erectile function and to measure the effect of age, BMI, and ED on the susceptibility to COVID-19. Sample size was calculated based on a 28% prevalence of ED among the COVID+group, using a 0.8 effect size (accounting for a large effect size), with 1:3 ratio, α = 0.05, and power 0.95. According to these 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. According to the suggested propensity score matching approach detailed above, 100 subjects from the 985 sexually active men belonging to the Sex@COVID cohort were retrieved: 25 subjects reported having contracted COVID-19 (COVID+), and a matching sample (based on age, BMI, and GAD-7 and PHQ-9 scores) of 75 subjects was recruited among those having no history of SARS-CoV-2 infection prior to filling the Sex@COVID survey (COVID-). Descriptive data of the study population are reported in Table 1 . According to propensity score matching, no statistically significant difference was found for age, GAD-7 and PHQ-9 scores, and BMI between the two groups. The prevalence of ED was higher in the COVID+group (7/25, 28%) than in the COVID-group (7/75, 9.33%; p-value 0.0274) ( Figure 1 ). Logistic regression models confirmed the association of COVID-19 with ED of COVID-19 on the development of ED (Table 2) : 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 ( 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] [25] [26] [27] [28] [29] [30] and to the present date, there seems to be no definite evidence of the presence of SARS-CoV-2 in seminal fluid 31, 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 on erectile function might be an additional cause of worry in COVID-19 patients. In the present study, to our best knowledge, we investigated for the first time the possible association between erectile function and COVID-19 in a real-life setting. Results of our study agree with the pathophysiological mechanisms linking ED, endothelial dysfunction, and COVID-19. By performing propensity score matching, we removed the possible bias resulting from age and BMI, factors which contribute to both increased prevalence of ED 13, 14 and increased susceptibility to COVID-19. 15 Based on the presented evidence and on similarities to previous coronavirus diseases, ED could therefore be both a short-term and a long-term complication of COVID-19. The potential association between ED and COVID-19 might increase awareness of the importance of personal protective equipment, such as masks, and social distancing in a harm reduction perspective for long-term consequences. 70 The use of masks as devices for the prevention of sexual dysfunctions is perhaps a bit stretched, but at present 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." 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 erectile impairment, or an aggravating factor for its progression to more severe forms. Likewise, subjects with ED should consider their erectile impairment as a sign of possible underlying conditions which could None. The authors declare no competing interests for the present study. Emmanuele A. Jannini https://orcid.org/0000-0002-5874-039X The trinity of COVID-19: immunity, inflammation and intervention COVID-19 cytokine storm: the interplay between inflammation and coagulation Prevalence of asymptomatic SARS-CoV-2 infection: a narrative review Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections The science underlying COVID-19: implications for the cardiovascular system COVID-19 pandemic acute respiratory distress syndrome survivors: pain after the storm? Endothelium infection and dysregulation by SARS-CoV-2: evidence and caveats in COVID-19 COVID-19 is, in the end, an endothelial disease The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection ED2: erectile dysfunction = endothelial dysfunction The interface of systems medicine and sexual medicine for facing non-communicable diseases in a genderdependent manner Addressing male sexual and reproductive health in the wake of COVID-19 outbreak Erectile dysfunction in aging male Lifestyles and sexuality in men and women: the gender perspective in sexual medicine Covid-19: Why are age and obesity risk factors for serious disease? COVID-19 and obesity: dangerous liaisons Benefits of sexual activity on psychological, relational, and sexual health during the COVID-19 breakout Validation and standardization of the Generalized Anxiety Disorder Screener (GAD-7) in the general population The PHQ-9: validity of a brief depression severity measure Factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019 Inventories for male and female sexual dysfunctions Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction Absence of 2019 novel coronavirus in semen and testes of COVID-19 patientsdagger No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019 Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab Assessment of SARS-CoV-2 in human semen-a cohort study Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients Absence of SARS-CoV-2 in semen of a COVID-19 patient cohort Clinical characteristics and results of semen tests among men with coronavirus disease 2019 SARS-CoV-2 infection, male fertility and sperm cryopreservation: a position statement of the Italian Society of Andrology and Sexual Medicine (SIAMS) (Societa Italiana di Andrologia e Medicina della Sessualita) SARS-CoV-2 presence in seminal fluid: Myth or reality Impact of the COVID-19 pandemic on partner relationships and sexual and reproductive health: Cross-sectional, online survey study Changes in sexuality and quality of couple relationship during the COVID-19 lockdown Angiotensinconverting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor SARS-CoV-2, SARS-CoV, and MERS-COV: a comparative overview SARS: prognosis, outcome and sequelae Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury The novel angiotensinconverting enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis Pathological findings in the testes of COVID-19 patients: clinical implications Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis Testicular changes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study COVID-19 and the endocrine system: exploring the unexplored COVID-19 pneumonia causes lower testosterone levels SARS-CoV-2 pneumonia affects male reproductive hormone levels: a prospective, cohort study A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment-a systematic review Endocrine evaluation of erectile dysfunction The relationship between circulating testosterone and inflammatory cytokines in men Immunothrombosis in severe COVID-19 Endothelial cell infection and endotheliitis in COVID-19 Erectile dysfunction From inflammation to sexual dysfunctions: a journey through diabetes, obesity, and metabolic syndrome SARS-CoV-2 myocarditis: what physicians need to know Cardiovascular manifestations of COVID-19 infection Pulmonary fibrosis secondary to COVID-19: a call to arms? Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy Looking ahead and behind at supplemental oxygen: a qualitative study of patients with pulmonary fibrosis Hemoglobin, iron, and hypoxia beyond inflammation. A narrative review Potential mechanisms for COVID-19 induced anosmia and dysgeusia Anosmia in COVID-19: mechanisms and significance Olfactory sensitivity and sexual desire in young adult and elderly men: an introductory investigation Olfaction is associated with sexual motivation and satisfaction in older men and women Sexual desire after olfactory loss: quantitative and qualitative reports of patients with smell disorders Olfactory function relates to sexual experience in adults Subclinical erectile dysfunction: proposal for a novel taxonomic category in sexual medicine Redefining a sexual medicine paradigm: subclinical premature ejaculation as a new taxonomic entity Harm reduction in sexual medicine Erectile dysfunction Clinical and metabolic evaluation of subjects with erectile dysfunction: a review with a proposal flowchart The 2018 revision to the process of care model for evaluation of erectile dysfunction People smoke for nicotine, but lose sexual and reproductive health for tar: a narrative review on the effect of cigarette smoking on male sexuality and reproduction