Ultrasound aspects of symptomatic versus asymptomatic forms of male accessory gland inflammation

Abstract Background The ultrasound (US) evaluation of the male sex accessory gland inflammation (MAGI) helps the clinicians to understand the severity of this condition, allowing them to distinguish the uncomplicated form (prostatitis) from the complicated ones (prostate‐vesiculitis and prostate‐vesiculitis‐epididymitis), as well as the unilateral from the bilateral forms, the fibrosclerotic and the hypertrophic‐congestive form. Objective This retrospective study aimed to evaluate the US features of MAGI patients with active symptoms compared to patients without sexual, voiding, and ejaculatory dysfunction. Materials/Methods To achieve this aim, an analysis of the prevalence of MAGI US criteria was carried out on a very large series of over 500 patients diagnosed with MAGI classified according to the different symptom profile evaluated through a dedicated questionnaire (previously conceived and published by our group) arbitrarily named “structured interview about MAGI” (SI‐MAGI) for sexual, voiding, and ejaculatory disorders reported by these patients. Results The results of this study revealed that US criteria most frequently detected in patients with severe urinary symptoms were the presence of areas of high echogenicity (almost exclusively in the periurethral prostatic zone) together with the presence of single or multiple areas of acinar ectasia of the prostate. The presence of seminal vesicles with polycyclic areas within the glandular lumen separated by hyperechoic septa represented US criterion most frequently detected in patients with severe spontaneous or post‐ejaculate pain. Finally, US criterion most frequently detected in patients with severe sexual dysfunction was the dilation of the periprostatic venous plexus, suggesting the hypothesis of a possible alternative therapeutic approach. Conclusion The data of the present study suggest that symptoms may associate with US signs in patients with MAGI. Also, specific US signs may associate with specific symptoms. Further studies are needed to understand whether patients with specific US signs may in turn benefit from a personalized therapeutic choice.


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.

| INTRODUC TI ON
Male accessory gland inflammation (MAGI) represents an acronym applied in clinical practice to describe the inflammations of the male accessory sex glands. In detail, prostate, epididymis, and seminal vesicles represent the anatomical sites potentially involved. MAGI, which usually has a chronic course, is able to negatively impact on the semen quality and can associate with a wide range of symptoms. [1][2][3][4][5] Diagnosis of MAGI is based on widely accepted clinical and laboratory criteria. 2,3,5,6 However, ultrasound (US) examination can provide details regarding the anatomical extension of the inflammatory process. 1,[7][8][9] The symptoms of patients with MAGI are not easily assessable and, notably, patients are falsely asymptomatic in several cases. The true reasons for the first clinical counseling could concern different issues, such as ejaculatory or voiding function, quality of sexual life, and chronic pelvic pain. 10 For this reason, we have previously adopted a specific questionnaire, arbitrarily named "structured interview about MAGI" (SI-MAGI), which includes different symptom domains and which could guide the clinician through the collection of the patients' medical history. 10 The first level of clinical evaluation should include: 1. an active collection of medical history (supplemented by questionnaire); 2.
physical andrological examination (with careful evaluation of the prostatic region through anorectal digital exploration); 3. semen analysis; 4. microbiological evaluation of secretion obtained after prostate massage. 1,3 The incomplete application of this procedure involves a diagnostic underestimation of the diagnosis of MAGI and explains the reasons for the different frequency reported in the various clinical studies. [11][12][13] In our experience, together with varicocele, MAGI represents the condition with the greatest prevalence in infertile patients. The incompleteness of the clinical evaluation of patients with MAGI may be likely ascribed to the lack of urologic and endocrinologic expertise. Indeed, these kinds of patients usually refer to endocrinologists or urologists. While endocrinologists may have difficulty with anorectal digital exploration, urologists may have an incomplete seminological training being more trained in surgical practice. 1 Indeed, endocrinologists with urologic expertise or, in contrast, urologists with endocrinologic competence, are lacking.
In clinical practice, the application of US criteria for the study of infertile patients is generally limited to the exclusion of obstructive azoospermia. 14 In our experience, the targeted use of US evaluation of patients with MAGI allows us to make a diagnosis of the anatomical site, helping in the distinction of unilateral or bilateral forms, or in the description of forms with better or worse seminological prognosis. It can also help in the differential diagnosis of some highly associated sexual dysfunctions, such as acquired premature ejaculation or the evaluation of cases of hemospermia. 1 Based on the premises, the present study evaluated the US differences between symptomatic and asymptomatic patients with diagnosis of MAGI (according to the questionnaire scores). To accomplish this, the US features of patients with MAGI were retrospectively reviewed, and the findings were analyzed according to the SI-MAGI questionnaire score.

| MATERIAL S AND ME THODS
The outpatient medical records of 1320 patients with a diagnosis of MAGI were retrospectively evaluated. Patients referred to the Andrology and Endocrinology Center for infertility, varicocele, fertility checking, phimosis, urogenital infection or inflammation, and scrotal pain.
The diagnosis of MAGI was established using the criteria of the World Health Organization. Particularly, patients were diagnosed for MAGI in case of oligo-, astheno-, and/or teratozoospermia associated with one factor A plus one factor B, or one factor A plus one factor C, or one factor B plus one factor C, or two factors C.
Factor A occurred in case of history positive for urinary infection, epididymitis, and/or sexually transmitted diseases, or in the presence of physical signs of urogenital inflammation (eg, thickened or tender epididymis, tender vas deferens, and/or abnormal digital rectal examination). Factor B occurred in case of abnormal prostate fluid expression and/or abnormal urine after prostatic massage.
Factor C occurred in case of ejaculatory signs of inflammation (leukocyte > 1 million/ml, culture with significant growth of pathogenic bacteria, abnormal appearance, increased viscosity, increased pH, and/or abnormal biochemistry of the seminal plasma). [1][2][3] Patients were enrolled in the period between January 2011 and January 2020 at the Andrology and Endocrinology Center of the University of Catania. The US of the male accessory glands was performed by specialists specifically trained in the identification of suggestive US feature of MAGI (SLV, AEC, AC, MC).
All patients for whom access to the US report was not available or who had not compiled or completed the SI-MAGI questionnaire were excluded from the analysis. Figure S1 summarizes the questions of the questionnaire administered to patients.
Patients were grouped basing on the specific symptom they complained of. Specifically, the US characteristics of 525 patients with MAGI aged between 20 and 43 years were analyzed, and patients were divided into: 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.

| 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 For each group, the observational frequency of the various US criteria adopted for the diagnosis of MAGI was calculated (no. 6 US criteria suggestive for chronic prostatitis; no. 8 US criteria suggestive for chronic vesiculitis; no. 6 US criteria suggestive for chronic epididymitis). 1,7 Within Group C, a further distinction was made regarding the observational frequency of the aforementioned US criteria detected in men with erectile dysfunction in the achievement and maintenance phase and in patients with ejaculatory disorders.
A series of 120 patients with MAGI between 18 and 48 years without symptoms (questionnaire scores lower than the minimum in all domains of the questionnaire) were considered as the control group.

| Statistical analysis
Results are shown as percentage. Statistical analysis was performed by one-way analysis of variance (ANOVA), followed by the Duncan's multiple range test, using SPSS 22.0 for Windows (22.0, SPSS Inc). A p value < 0.05 was accepted as statistically significant.

| Ethical approval
This study was conducted at the Division of Andrology and Endocrinology of the teaching hospital "G. Rodolico", University of Catania (Catania, Italy). informed written consent was obtained from each participant after full explanation of the purpose and nature of all procedures used. The study has been conducted in accordance with the principles expressed in the Declaration of Helsinki.

| RE SULTS
US criteria most frequently detected in patients with severe urinary symptoms (Group A) were the presence of areas of high echogenicity (also defined as calcifications in clinical practice) together with the presence of single or multiple areas of acinar ectasia of the prostate (box highlighted in yellow in Table 1. The combination of these two US criteria was found in 58% of cases. Among 100 patients with this US combination, 90% (90) of them showed a periurethral localization of the calcifications.  Table 1. Compared to patients with severe urinary symptoms and severe sexual dysfunction, a higher frequency, but not statistically significant, of the following US criteria was found: areas of  Table 1.
Compared to patients with severe urinary symptoms and severe spontaneous or post-ejaculatory pain, a higher frequency, but not statistically significant, of the following US criteria was found: dilation of seminal vesicles maintained after ejaculation,changes in echogenicity of the epididymis; presence of hydrocele; epididymal dimensions unchanged after ejaculation.
Among the Group C patients, we restricted the analysis of the frequency of US criteria to patients who reported the following disorders to the questionnaire: erectile dysfunction in the achievement or maintenance phase, premature ejaculation, or delayed ejaculation. Finally, the green panels of Table 1 show the US criteria detected in patients with symptomatic MAGI with a significantly higher frequency than controls. Eleven US criteria out of twenty detectable were statistically more frequent in symptomatic MAGI compared to controls.

| DISCUSS ION
The results of this study suggest that the different array of symptoms of patients with MAGI associates with a specific US characterization. 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]

| 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 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]   Its muscle relaxant properties may be due to a direct action on the smooth muscle rather than by antagonizing muscarinic receptors.
There are no other studies in the literature regarding the possible therapeutic application in MAGI.
Finally, among patients suffering from erectile dysfunction, it would be useful to differentiate those who have difficulty in achieving from those who have difficulty in maintaining an adequate erection (potential anamnestic criterion for venous erectile dysfunction). 26 For the latter, the US evaluation of the prostate-vesicular region and a possible treatment of ectasias of the periprostatic venous plexus would also be useful in an expanded diagnostic and therapeutic framework.
For these patients, it could be proposed an interventional evaluation for a possible embolization of the periprostatic venous plexus which represents an option with few evidence in the scientific literature. Rebonato Figure S2.

CO N FLI C T O F I NTE R E S T
All authors declare no competing interests.  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.

AUTH O R' S CO NTR I B UTI
Orchitis and broad destruction of the testes were found in deceased 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. The Cochrane RoB 2.0 tool was not applicable, and the Newcastle-Ottawa Scale was not used due to the limited scope of the cohort studies among the included studies.

| ME THODS
The literature search in PubMed used the following search terms: