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Asian Journal of Urology xxx (xxxx) xxx

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9 Review 71
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12 Male genital damage in COVID-19 patients: 73
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14 Are available data relevant? 75
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Q4 Kharbach Youssef*, Khallouk Abdelhak 78
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Urology Department, Tangier University Hospital, Faculty of Medicine, Abdelmalek Essaâdi University, 81
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90000, Tangier, Morocco 82
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Received 25 April 2020; received in revised form 21 May 2020; accepted 10 June 2020 84
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27 KEYWORDS Abstract Over the past few weeks, we have observed increasing concern about the possible 89
28 impact of coronavirus disease 2019 (COVID-19) which is caused by SARS-CoV-2 virus (severe
COVID-19; 90
29 acute respiratory syndrome coronavirus 2) on male fertility. Precise mechanisms of male repro-
SARS-CoV-2; 91
30 ductive damages are still unclear, but it seems that high temperature resulting from persistent
Male genital system; 92
31 fever and triggering a secondary autoimmune response leading to an autoimmune orchitis are
Testis; 93
32 the most likely involved mechanisms. Also, angiotensin conversion enzyme 2 (ACE2) plays a
Male infertility 94
33 highly important role in cellular entry for SARS-CoV-2 and male genital system presents high 95
34 ACE2 expression. All these preliminary findings suggest that COVID-19 could impact men’s 96
35 reproductive health. Thus, we examined available data including published and unpublished 97
36 articles to assess the potential risk of COVID-19 in particular on the male reproductive system. 98
37 ª 2020 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. This 99
38 is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ 100
39 licenses/by-nc-nd/4.0/). 101
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1. Introduction [1,2]. Over the past few weeks, we have observed 106
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increasing concern about the impact of coronavirus disease 107
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2019 (COVID-19) caused by SARS-CoV-2 (severe acute res- 108
47 Many viruses such as mumps virus, hepatitis viruses B/C,
piratory syndrome coronavirus 2) on male fertility. Thus, we 109
48 herpes simplex virus, human papillomavirus, coxsackie
examined available data including published and unpub- 110
49 virus, influenza, HIV (human immunodeficiency virus) and
lished articles to assess the potential risk of COVID-19 in 111
50 SARS-CoV-1 (severe acute respiratory syndrome coronavirus
particular on the male reproductive system. 112
51 1) could infect the male genital system and impair fertility
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53 2. Viral threat to male fertility 115
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* Corresponding author. 116
55 It is known that viruses could infect the testis directly [2].
E-mail address: ykharbach@uae.ac.ma (K. Youssef). 117
56 Also, the male reproductive system has an immunosup-
Peer review under responsibility of Second Military Medical 118
57 pressive environment due to the bloodetestis barrier which
University. 119
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https://doi.org/10.1016/j.ajur.2020.06.005 121
60 2214-3882/ª 2020 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. This is an open access article under 122
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Youssef K, Abdelhak K, Male genital damage in COVID-19 patients: Are available data relevant?, Asian Journal of
Urology, https://doi.org/10.1016/j.ajur.2020.06.005
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2 K. Youssef, K. Abdelhak

1 might protect seminal viruses from immune surveillance cases observed in China and those outside China [5]. Male 63
2 [1]. For example, mumps viruses has high tropism for the genital system involvement is not clear yet. 64
3 testes, orichitis develops in 20%e30% of cases and could 65
4 destroy testicular parenchyma [1,2]. Main mechanisms of 5. Pathogenesis: how could SARS-CoV-2 infect 66
5 testis damage in mumps infection are unknown and remain 67
male genital system?
6 to be clarified [1,3]. However, the most common hypothesis 68
7 is that testis degeneration is attributed to an increase in 69
8 testicular temperature as an indirect effect of the inflam- Angiotensin conversion enzyme (ACE) converts angiotensin I 70
9 matory milieu [1]. to angiotensin II in the renin-angiotensin-aldosterone sys- 71
10 Also, Xu et al. [2] conducted a study on autopsy specimens tem (RAAS) [11]. ACE2 is an endogenous counter-regulator 72
11 of testis that were obtained from six patients who died of of classic ACE system that deactivates the angiotensin II 73
12 SARS-CoV-1 infection (SARS-CoV-2 is closely related to SARS- [11]. 74
13 CoV-1 with above 85% identity [4]). All six cases had orchitis. First, the SARS-CoV-2 enters into human cells using ACE2 75
14 Xu et al. [2] noticed a leukocyte infiltration in the SARS-CoV-1 as receptor which have very similar spike protein three- 76
15 testis that could affect the function of Leydig cells, damage dimensional (3D) structures with strong binding affinity 77
16 the blood-testis barrier, and destroy directly the seminiferous [12]. ACE2 is present with relatively high expression in 78
17 epithelium. Furthermore, symptoms of orchitis in these pa- respiratory epithelial cells, alveolar cells type I and II, oral 79
18 tients were not observed or reported clinically. cavity, kidney, testis, and intestines [11]. Thus, human cells 80
19 Precise mechanisms of male reproductive damages in with ACE2 expression are probably targets of SARS-CoV-2 81
20 viral infection are still unclear [1], but it seems that high infection [13]. However, it should still be noted that 82
21 temperature resulting from persistent fever and triggering SARS-CoV-2 invasion is not just about ACE2 and there is 83
22 a secondary autoimmune response leading to an autoim- probably other vulnerable organs [13]. It seems that high 84
23 mune orchitis are the most likely mechanisms of male temperature resulting from persistent fever and triggering 85
24 reproductive system damage [1e3]. a secondary autoimmune response leading to an autoim- 86
25 All this data suggest that male urogenital system may be mune orchitis are the most likely involved mechanisms. 87
26 a potential target of SARS-CoV-2. 88
27 6. SARS-CoV-2 and male genital system 89
28 3. Epidemiology 90
29 Preliminary findings from studies that are, unfortunately, 91
30 not peer-reviewed and published as preprints, are linking 92
SARS-CoV-2 was the virus causing the disease named COVID-
31 SARS-CoV-2 to male infertility [14e16]. But, it seems to us 93
19 [5]. This virus is the seventh infecting humans member of
32 that it is premature to make definitive conclusions at 94
the Coronovirinae subfamily which are enveloped, single
33 present. 95
positive-strand RNA viruses [5]. It is listed in the World
34 Ma et al. [14] conducted a study on 81 reproductive-aged 96
Health Organization (WHO) Blueprint list for priority path-
35 men with SARS-CoV-2 infection and 100 age-matched 97
ogens for research due to its epidemic potential [5].
36 healthy men. They found significantly elevated luteinizing 98
It is also the most contagious [6], and is now declared as
37 hormone (LH) level, but decreased testosterone/LH and 99
a Public Health Emergency of International Concern by the
38 follicle-stimulating hormone (FSH)/LH ratios levels in 81 100
WHO [7]. As of 11 Jun 2020, there have been 7 221 717
39 men with COVID-19 which is suggesting potential hypo- 101
confirmed cases with 411 818 deaths [7]. Interestingly,
40 gonadism. But it seems to us that these findings cannot 102
COVID-19 has a lethality that continuously rises with age
41 affirm whether this alteration is due to a direct or indirect 103
unlike other respiratory diseases that have a U-shaped
42 effect of SARS-CoV-2 on the testes. Previous studies re- 104
lethality curve [5].
43 ported that high temperature contributed to germ cell 105
Limited data are available, at this stage of the
44 destruction [2], and high fever in COVID-19 might have an 106
pandemic, concerning the involvement of male genital
45 indirect effect on testicular dysfunction. Furthermore, LH 107
system in COVID-19 patients.
46 release is pulsatile and shows circadian rhythm. We think 108
47 that there is a biased sampling in Ma et al. study. Actually, 109
48 4. Clinical characteristics COVID-19 patients and control group should be tested at the 110
49 same time of the day, otherwise, widely varying average 111
50 Almost 58.1% of patients are males with a median age of levels of LH will be observed. 112
51 47e49 years and increased severity in the elderly [6,8,9]. Also, Fan et al. [15] and Shen et al. [16] found high ACE2 113
52 Also, the complete clinical manifestation is not clear yet expression in testis (both germ cells and somatic cells) 114
53 [8]. COVID-19 patients present a wide spectrum of clinical suggesting potential tropism of SARS-CoV-2 to testicular 115
54 features [5]. They commonly report fever, respiratory tissues. Shen et al. [16] performed bioinformatics tools to 116
55 symptoms, myalgia or fatigue [8,9]. Most patients present analyze scRNA-seq data of testis for three normal young 117
56 cytokine storm that might cause immune damage [10]. This males, two adult normal males, seven obstructive azoo- 118
57 uncontrolled reaction of the immune system can damage spermia and one nonobstructive azoospermia. They showed 119
58 most vital organs and lead to acute kidney injury, various that the expression level of ACE2 was related to the age and 120
59 degrees of liver damage, acute cardiac injury, and multiple the peak of positive rate was at 30 years old [16]. These 121
60 organ failure [10]. Previous exposure to non-SARS-CoVs in findings are confirmed by the interesting study of Liu et al. 122
61 China could explain the disparity between the severity of [17] published scRNA-seq data, including seven obstructive 123
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Please cite this article as: Youssef K, Abdelhak K, Male genital damage in COVID-19 patients: Are available data relevant?, Asian Journal of
Urology, https://doi.org/10.1016/j.ajur.2020.06.005
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Male genital damage in COVID-19 patients 3

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47 Conflicts of interest cell transcriptome analysis of the novel coronavirus (SARS- 109
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Please cite this article as: Youssef K, Abdelhak K, Male genital damage in COVID-19 patients: Are available data relevant?, Asian Journal of
Urology, https://doi.org/10.1016/j.ajur.2020.06.005