When to ask for an MRI of the scrotum

Abstract Background Multiparametric MRI (mpMRI) of the scrotum has been established as a useful second‐line diagnostic tool for the investigation of scrotal diseases. Recently, recommendations on clinical indications for scrotal MRI were issued by the Scrotal and Penile Imaging Working Group of the European Society of Urogenital Radiology. Objective To update current research on when to ask for an MRI of the scrotum. Methods PubMed database was searched for original articles and reviews published during 2010–2021. Results Eighty‐three articles fulfilled the search criteria. Scrotal MRI is mainly recommended after inconclusive US findings or inconsistent with the clinical examination and should be asked in the following cases: differentiation between intratesticular and paratesticular lesions (in rare cases of uncertain US findings), characterization of paratesticular and intratesticular lesions (when US findings are indeterminate), discrimination between germ cell and sex cord‐stromal testicular tumors, local staging of testicular malignancies (in patients planned for testis‐sparing surgery), differentiation between seminomas and non‐seminomatous tumors (when immediate chemotherapy is planned and orchiectomy is delayed), assessment of acute scrotum and scrotal trauma (rarely needed, in cases of non‐diagnostic US findings) and detection and localization of undescended testes (in cases of inconlusive US findings). Although preliminary data show promising results in the evaluation of male infertility, no established role for mpMRI still exists. Conclusion Multiparametric MRI of the scrotum, by assessing morphologic and functional data represents a valuable problem‐solving tool, helping to improve our understanding on the nature of scrotal pathology and the process of spermatogenesis. The technique may improve patient care and reduce the number of unnecessary surgical procedures.


| RE SULTS AND D ISCUSS I ON
After reviewing the studies retrieved from the database, citations and references were added based on a review of the title or abstract ( Figure 1). Fourteen studies were eligible and were included in this study, with 12 studies detecting SARS-CoV-2 in the male reproductive tract, 3 determining the impact of COVID-19 on sperm quality and 3 exploring pathological changes in the testes of COVID-19 patients.

| Detection of COVID-19 in the male reproductive tract
Twelve studies investigated the presence of SARS-CoV-2 in the male reproductive tract (eg semen, prostatic secretion or testicular tissue) and are shown in Table 1. Most studies were cross-sectional in design and included mainly Chinese subjects. In brief, ten of 12 studies reported that none of the participants had SARS-CoV-2 RNA 2 | TSILI eT aL.

| INTRODUC TI ON
Color Doppler ultrasonography (CDUS) represents the imaging modality of choice for the initial assessment of scrotal pathology. [1][2][3][4][5][6][7][8][9] It is a safe, widely available, easily performed, inexpensive technique and does not use ionizing radiation. CDUS is highly sensitive and accurate in the assessment of scrotal diseases, often guiding proper treatment. Current guidelines, including the National Comprehensive Cancer Network and the European Association of Urology, advocate the use of US for the evaluation of a suspected testicular mass. 8,10 However, conventional US has limitations associated with operator-dependence, relatively small field of view, and difficulties in tissue characterization. An accurate differentiation of the nature of scrotal lesions, especially lesions of small size is not always possible, based on sonographic features. [11][12][13] Diagnoses such as a minor tear in the tunica albuginea in blunt scrotal trauma or chronic epididymoorchitis and partial or delayed torsion may sometimes be missed on sonography. [14][15][16][17][18] The introduction of multiparametric US (including Color Doppler US) real-time elastography and contrast-enhanced US into clinical practice has improved the diagnostic performance of standard US in the investigation of scrotal diseases. [19][20][21][22][23] Multiparametric MRI (mpMRI) of the scrotum has emerged as a valuable supplemental technique for the investigation of scrotal pat hology. [7][8][9]11,12,15, Scrotal MRI due to the wide field of view and multiplanar capabilities depicts in excellent anatomic detail both testes, epididymides, spermatic cords, and inguinal regions. The technique provides high soft-tissue contrast, high sensitivity for contrast enhancement, and functional information, it is less dependent on operator compared to US and does not include ionizing radiation.
Scrotal MRI allows differentiation between intratesticular and paratesticular lesions and accurate tissue characterization, by showing the presence of fat, hemorrhage, fibrosis, fluid content, and contrastenhancing tissue. MRI findings may narrow differential diagnosis, helping in planning more precise treatment strategies and reducing the need of unnecessary surgical explorations. [7][8][9]11,12,15, Recently, the Scrotal and Penile Imaging Working Group (SPIWG) appointed by the board of the European Society of Urogenital Radiology (ESUR) has produced recommendations on clinical indications for scrotal MRI, based on literature published before 2016 and combined expertise of the group. 24 MRI of the scrotum is primarily recommended for the characterization of paratesticular and intratesticular lesions in questionable cases, when US findings are indeterminate and for the identification and localization of undescended testes. The technique may provide valuable information in the preoperative planning, local staging, and histologic characterization of testicular germ cell neoplasms (TGCNs), in selected cases. It represents a supplemental, problem-solving tool for the investigation of acute scrotum and scrotal trauma, following equivocal US findings. 24 Scrotal MRI may prove reliable in differentiating between TGCNs and sex cord-stromal tumors, specifically in characterizing Leydig cell tumors (LCTs), allowing the adoption of conservative surgery and active surveillance, in compliant patients, as treatment options. 24,47 The protocol of scrotal MRI should include axial T1-weighted imaging (T1WI), axial and coronal T2-weighted imaging (T2WI), axial diffusion-weighted imaging (DWI), and coronal subtracted dynamic contrast-enhanced (DCE) imaging. 24 In this review, we summarize current research on when to ask for an MRI of the scrotum.

Lesion localization: intratesticular versus paratesticular
The determination of a scrotal lesion location is of outmost importance, since intratesticular solid mass lesions are malignant in more than 95% of cases and paratesticular mass lesions are more often benign. MRI is highly accurate in differentiating between intratesticular and paratesticular lesions, although rarely needed, since lesion localization is often a straightforward diagnosis for US. 24

| INTRODUC TI ON
Since the first case of coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported in Wuhan, China, it has rapidly spread and affected more than 21 million people worldwide as of 17 August 2020. 1 SARS-CoV-2 uses angiotensin-converting enzyme II (ACE2) to enter host cells, similar to SARS-CoV, which emerged 18 years ago. 2 COVID-19 induces respiratory-predominant multiorgan dysfunction, including myocardial, renal, enteric and hepatic dysfunction, which coincides with the tissue expression of ACE2. 3 Meanwhile, several studies have shown that ACE2 is expressed in human testes (eg spermatogonia, Leydig cells and Sertoli cells), 4,5 suggesting that the testes may be another organ affected by COVID-19.
Numerous viruses have been detected in human semen. 6 Viruses may persist in semen and last longer in seminal fluid than in other body fluids due to the immune privilege of the testes and the contribution of the blood-testes barrier to resistance to therapeutic agents. 7,8 Semen may also have higher loads of viruses, such as Zika virus, than blood. 9,10 Therefore, the testes may act as a reservoir of virus, which may cause imprecise evaluation of viral clearance in patients. Viruses, including Zika virus, Ebola virus, cytomegalovirus and human immunodeficiency virus (HIV), have been isolated from semen and can be sexually transmitted. 6,11,12 Furthermore, some viruses (eg HIV, Zika virus, herpes simplex virus (HSV) and human papillomavirus) can adhere to or be internalized by spermatozoa, 7,13 which may pose a risk for embryonic infection and cause adverse reproductive outcomes.
On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.
Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35,37 while the pathological characteristics in survivors remain unknown. In this review, we summarize the current research focusing on the effects of COVID-19 on male reproduction from the following 3 aspects: detection of SARS-CoV-2 in the male reproductive tract, determination of the impact of COVID-19 on sperm quality and exploration of pathological changes in the testes of COVID-19 patients. We further discuss the discrepancies and summarize the unknown topics, which we believe will be helpful for future research. MRI is recommended in cases of questionable US findings, including patients with markedly enlarged scrotum. 25 MRI also helps in the differentiation between a scrotal lesion originating from testicular tunica and peripheral seminiferous tubules, when this is difficult to define sonographically. The detection of a thin, hypointense, well-defined halo, best depicted on T2WI, lying between the lesion and the adjacent testicular parenchyma, corresponding to the tunica albuginea, helps to suggest lesion origin. [5][6][7][8]24,25,29,33,[42][43][44][45] MRI proved to be capable of identifying the correct lesion location with sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of 100%, each, in a study including 84 patients with suspected scrotal masses. 35

Paratesticular lesions
Paratesticular solid tumors are rare and more often benign, with an incidence of malignancy approximately of 3%. Accurate characterization of the nature of paratesticular lesions is of outmost importance to allow planning of a conservative treatment in benign lesions, such as surveillance, excision, or TSS. The US characteristics of paratesticular tumors are usually overlapping, and therefore, scrotal MRI is strongly recommended as a valuable supplemental technique, to define lesion location and extent and to suggest a possible histologic diagnosis. 6,8,29,30,33,36,[42][43][44][45] Although the sonographic diagnosis of an epididymal cyst or a tunica albuginea cyst is often straightforward, concerns may arise in the presence of complex cysts. In these cases, absence of enhancement on MRI confirms an avascular mass and the diagnosis of benignity. MRI with multiplanar imaging also helps in suggesting lesion location. 30,36 When differentiation between an adenomatoid tumor and a peripheral intratesticular mass is ambiguous on US, scrotal MRI is highly recommended to suggest paratesticular origin. Surgery in paratesticular adenomatoid tumors includes intraoperative frozen section biopsy and local resection, whereas in intratesticular adenomatoid tumors, TSS is planned. 6,8,29,33,36,43,44,111 On MRI, adenomatoid tumor usually appears hypointense on T2WI, with slow or decreased contrast enhancement, relative to the normal testis ( Figure 2). 30

| RE SULTS AND D ISCUSS I ON
After reviewing the studies retrieved from the database, citations and references were added based on a review of the title or abstract

| Detection of COVID-19 in the male reproductive tract
Twelve studies investigated the presence of SARS-CoV-2 in the male reproductive tract (eg semen, prostatic secretion or testicular tissue) and are shown in Table 1 Occasionally, the mediastinum testis, supernumerary epididymis, and bridging vessels between the normal testis and the extra-testicle may be seen. 6,8,29,30,44,116,117  fat, fibrous tissue, blood products, myxoid, and granulation tissue . [6][7][8][9]11,12,14,[24][25][26][27][28][29][30][33][34][35][36][37]42,48,[50][51][52][53]56 The overall accuracy of MRI in the characterization of benign testicular diseases has been reported 87.5%, and the NPV 100%. 48 The absence of contrast enhancement represents a highly sensitive sign in characterizing the benign nature of intratesticular lesions. 6,48 The sonographic findings of testicular cysts and TERT are usually typical, and therefore, MRI is rarely needed. However, it is recommended when differential diagnosis from cystic neoplasms, including cystic teratomas and papillary adenocarcinomas of the rete testis is difficult. 7,11,29,30,36,119 Typical MRI criteria, including the presence of tubular cystic structures, of watery signal, involving the mediastinum testis, with absence of solid elements and contrast enhancement, are used for the diagnosis of TERT. 7,11,29,30 The sonographic diagnosis of testicular fibrosis is usually diffi- On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.
Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35 on sperm quality and exploration of pathological changes in the testes of COVID-19 patients. We further discuss the discrepancies and summarize the unknown topics, which we believe will be helpful for future research.   On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.

| reprodu
Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35 on sperm quality and exploration of pathological changes in the testes of COVID-19 patients. We further discuss the discrepancies and summarize the unknown topics, which we believe will be helpful for future research.

| RE SULTS AND D ISCUSS I ON
After reviewing the studies retrieved from the database, citations and references were added based on a review of the title or abstract

| Detection of COVID-19 in the male reproductive tract
Twelve studies investigated the presence of SARS-CoV-2 in the male reproductive tract (eg semen, prostatic secretion or testicular tissue) and are shown in Table 1 On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.
Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35   in TGCNs, detected as an early, strong enhancement, followed by a gradual de-enhancement ( Figure 4). 53,57 Although Recently, texture analysis was used to characterize testicular le-

| RE SULTS AND D ISCUSS I ON
After reviewing the studies retrieved from the database, citations and references were added based on a review of the title or abstract

| Detection of COVID-19 in the male reproductive tract
Twelve studies investigated the presence of SARS-CoV-2 in the male reproductive tract (eg semen, prostatic secretion or testicular tissue) and are shown in Table 1. Most studies were cross-sectional in design and included mainly Chinese subjects. In brief, ten of 12 studies reported that none of the participants had SARS-CoV-2 RNA 8 | TSILI eT aL.
solid testicular mass lesions, detected as incidental findings.
Histologic diagnosis is benign in approximately 80% of these cases, and LCTs represent the commonest pathology. 47,126 TSS is highly recommended in these patients. When a sex cord-stromal tumor is suggested by frozen section examination, radical orchiectomy may be avoided. 10,47,127 Although no established imaging criteria exist, mpMRI may help in the characterization of LCTs and in the differentiation from TGCNs, and especially testicular seminomas. 6,7,13,24,47,59,68,77 MRI features suggesting the diagnosis of LCTs include a well-defined, intratesticular mass, markedly hypointense on T2WI, homogeneously enhancing after gadolinium administration, with early, strong enhancement, followed by slow de-enhancement ( Figure 5). 13 MRI characteristics of testicular seminomas include an ill-defined tumor, slightly hyperintense, and hypointense on T1WI and T2WI, respectively, with gradual contrast enhancement and absence of deenhancement ( Figure 4). 13 Semiquantitative and quantitative DCE-MRI parameters have been reported useful in the characterization of small, impalpable solid testicular tumors. 68 LCTs have lower percentage of peak enhancement, wash-in-rate, volume transfer constant, and rate constant, and shorter time to peak when compared to seminomas. 68 Moreover, a recent retrospective study reported that benign testicular stromal tumors have smaller size, more hypointense T2 signal, higher ADC, and more homogeneous enhancement, when compared to malignant stromal and non-stromal testicular tumors. 77

Local staging and histologic characterization of TGCNs
Radical inguinal orchiectomy, with removal of the entire testis containing tumor along with the spermatic cord to the level of the internal inguinal ring, is the treatment of choice for testicular malignancies and should be performed within a week of initial diagnosis. 7 (Figure 4). Non-seminomatous GCNs are usually heterogeneous, with inhomogeneous enhancement. 128,129 A hypointense rim, corresponding to fibrous capsule on pathology is seen more common on non-seminomas ( Figure 6). 129 ADC is also efficient in characterizing TGCNs. Seminomas usually

F I G U R E 5 Leydig cell tumor. (A)
Axial T2WI demonstrates small right intratesticular mass (arrow), of low signal. On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.
Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35   have lower ADC, when compared to non-seminomas (Figures 4 and   5). 57 A cut-off ADC of 0.68 × 10 −3 mm 2 /s is reliable in differentiating seminomas from non-seminomatous tumors. 63 Table 3 shows common testicular neoplasms for which mpMRI is useful.

| reprodu
Recently, whole-lesion ADC histogram analysis and T2WI-based radiomics provided promising results in the characterization of the histologic type of TGCNs. 69,79 A significant reduction in the median 10th, 25th, 50th, 75th, and 90th percentiles and the mean, minimum, and maximum ADC, and a significant increase in the median kurtosis and skewness of ADC was found in seminomas compared with non-seminomas, in a retrospective study of 24 TGCNs. 69 In particular, the 10th percentile ADC yielded the highest AUC, with a sensitivity and specificity of 100% and 92.86%, respectively. 69 T2WI-based radiomics also proved helpful to discriminate between seminomas and non-seminomas. 79 Characterization of the histologic type of TGCNs is rarely needed, in patients diagnosed with disseminated disease and/or lifethreatening metastases, in whom immediate chemotherapy is given.
In these cases, MRI is strongly recommended. 24 Recently, MRI has been reported helpful in the diagnosis of bell clapper deformity (BCD), an important risk factor for testicular torsion. The detection of BCD may also help in diagnosing intermittent testicular torsion. The "split sign" has been described as useful in diagnosing BCD, detected as a hyperintense T2 area placed between the posterior aspect of the epididymis and the scrotal wall. 83 Multiparametric MRI may complement the sonographic evaluation in patients with acute scrotal pain due to testicular torsion, as a confirmatory examination, helping to determine when and how to perform surgical intervention. 14 On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.
Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35 on sperm quality and exploration of pathological changes in the testes of COVID-19 patients. We further discuss the discrepancies and summarize the unknown topics, which we believe will be helpful for future research.

| RE SULTS AND D ISCUSS I ON
After reviewing the studies retrieved from the database, citations and references were added based on a review of the title or abstract ( Figure 1). Fourteen studies were eligible and were included in this study, with 12 studies detecting SARS-CoV-2 in the male reproductive tract, 3 determining the impact of COVID-19 on sperm quality and 3 exploring pathological changes in the testes of COVID-19 patients.

| Detection of COVID-19 in the male reproductive tract
Twelve studies investigated the presence of SARS-CoV-2 in the male reproductive tract (eg semen, prostatic secretion or testicular tissue) and are shown in Table 1. Most studies were cross-sectional in design and included mainly Chinese subjects. In brief, ten of 12 studies reported that none of the participants had SARS-CoV-2 RNA 10 | TSILI eT aL.
MRI may be used as a second-line imaging examination in the assessment of complicated scrotal infections and inflammations. Scrotal MRI provides a reliable map, regarding the extent of the disease, especially when there is concern for Fournier's gangrene, helping in planning percutaneous drainage or surgical debridement. 8,18,28,43 The technique also may be used to suggest the diagnosis of a scrotal abscess, occasionally difficult to differentiate from other testicular pathologies, including testicular torsion, hematoma, or tumor. 28,43 At MRI, abscess displays a hyperintense T2 signal, peripheral enhancement, and markedly restricted diffusion. MRI also enables excellent depiction and mapping of scrotal skin or perineum sinus tracts or fistulous tracts. 28,43,134 MRI limitations in the assessment of acute scrotum should be acknowledged, including limited availability of an urgent MRI study and possible need for anesthesia in young patients.

Scrotal trauma
MRI is rarely needed in cases of scrotal trauma, as sonography is often diagnostic. 1,2,4,5,24,135 However, in cases equivocal for the diagnosis of testicular rupture at US, MRI represents a valuable adjunct tool. Multiplanar T2WI greatly assesses the integrity of the tunica albuginea, in patients with blunt scrotal trauma. 18 On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.
Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35 105 NOA testes with positive sperm retrieval often have higher choline, creatine, and myo-inositol levels, when compared to NOA testes with negative results post-mTESE ( Figure 7).

| reprodu
Choline proved the most sensitive metabolite in predicting the probability of finding spermatozoa, before mTESE. An increase in glutamate also has been observed in NOA testes with failed sperm retrieval. 97,105,108 Furthermore, recently testicular fat deposition was measured using the fat fraction map of mDIXON Quant sequence in middleaged overweight patients, including infertile and normal population. 109 The technique proved a reliable tool for the measurement of testicular fat deposition, enabling an accurate diagnosis and monitoring of male infertility. 109

| RE SULTS AND D ISCUSS I ON
After reviewing the studies retrieved from the database, citations and references were added based on a review of the title or abstract ( Figure 1). Fourteen studies were eligible and were included in this study, with 12 studies detecting SARS-CoV-2 in the male reproductive tract, 3 determining the impact of COVID-19 on sperm quality and 3 exploring pathological changes in the testes of COVID-19 patients.

| Detection of COVID-19 in the male reproductive tract
Twelve studies investigated the presence of SARS-CoV-2 in the male reproductive tract (eg semen, prostatic secretion or testicular tissue) and are shown in Table 1. Most studies were cross-sectional in design and included mainly Chinese subjects. In brief, ten of 12 studies reported that none of the participants had SARS-CoV-2 RNA

|
TSILI eT aL. us to improve our knowledge on the nature of scrotal masses and the extremely complex process of spermatogenesis.

CO N FLI C T O F I NTE R E S T
None.

AUTH O R ' S CO NTR I B UTI O N
AT and LM conceived and designed the study. MD and GE contrib-  on sperm quality and exploration of pathological changes in the testes of COVID-19 patients. We further discuss the discrepancies and summarize the unknown topics, which we believe will be helpful for future research.  On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.

| reprodu
Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35 on sperm quality and exploration of pathological changes in the testes of COVID-19 patients. We further discuss the discrepancies and summarize the unknown topics, which we believe will be helpful for future research.  On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.

| ME THODS
Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35 on sperm quality and exploration of pathological changes in the testes of COVID-19 patients. We further discuss the discrepancies and summarize the unknown topics, which we believe will be helpful for future research.