Stesura Seveso Archivio Italiano di Urologia e Andrologia 2024; 96(1):12113 1 SYSTEMATIC REVIEW long-term side effects, such as impact to the blood ves- sels, heart, lungs, kidneys, and brain. Also it was just dis- covered to have an effect on human testes, interfering with the production of vital male hormones such as testosterone (2). As a result of SARS-CoV-2 virus infection, systemic or local cytokine synthesis has the potential to inhibit Leydig cell differentiation, thereby compromising testicular cells by affecting testosterone production and the process of sper- matogenesis (3). This inflammatory process was further identified in the testicles of six males who died from SARS- CoV-2 (4). This study focused on total testosterone since it is one of the easiest and basic male sexual hormone param- eters to measure with acceptable precision in most hospital laboratories. Furthermore, the impact of lower testosterone is becoming an issue when there is concern regarding the long-term impact of the SARS-CoV-2 virus on decreased sexual desire and impaired male fertility. Other character- istics, such as free testosterone, Luteinizing Hormone (LH), and Follicle Stimulating Hormone (FSH), were included in the study as supporting data to better understand the pat- tern of male sexual hormone alterations. There is still no consensus or global agreement regarding the management of sexual and hormonal disorders after COVID-19 infection. Therefore, researchers are interest- ed in providing scientific evidence through a systematic review and meta-analysis focusing on the effects of SARS- CoV-2 virus infection on male sexual hormonal abnor- malities in patients after exposure to COVID-19. MATERIALS AND METHODS Protocol registration The protocol of this systematic review and meta-analysis is registered at PROSPERO (CRD42023445406) Search strategy and study selection This meta-analysis was made in accordance with the Preferred Reporting Items for Systematic Reviews and Meta- analyses (PRISMA) guidelines (5). The review topic was determined based on Population, Intervention, Comparison, Outcome (PICO) methods. The population was male over 18 years old without country or race restrictions. The Introduction: The COVID-19 can affect human testicles, thus will interfere the pro- duction of important male sexual hormone such as testosterone. Our study provides scientific evidence through systematic reviews and meta-analyses that focus on the effects of SARS- CoV-2 virus infection on male sexual hormonal disorders in patients post-exposure to COVID-19. Methods: This meta-analysis was made in accordance with the PRISMA guidelines. The outcomes of this study were the level of total testosterone, free testosterone, LH and FSH. Chi-square and I2 tests were used to evaluate heterogeneity between stud- ies. The standardized mean deviation (SMD) with 95% CI were used and analysis was performed using the Review Manager 5.4 software. Results: The four included studies reported a total of 256 patients with COVID-19 with time of follow-up time post COVID-19 varying from one month to 7 months. The mean age distribution in the study was 34-57 years old. Total testosterone level (SMD = -158.71; 95% CI= -205.30 – -112.12; p < 0.00001) was significantly higher at follow-up post COVID-19, while LH (SMD = 0.40; 95% CI = 0.15-0.65; p = 0.002) was lower. The free testosterone level and FSH level showed no significant difference between baseline and after following up post COVID-19. Conclusions: At follow up, the total testosterone level in patients with SARS-CoV-2 infection appeared to be elevated while LH was lower compared to the baseline. KEY WORDS: COVID-19; Male sexual hormones; Total testos- terone; Free testosterone; Luteinizing hormone; Follicle stimulat- ing hormone. Submitted 21 November 2023; Accepted 5 December 2023 INTRODUCTION Coronavirus disease, known as COVID-19, is an acute respiratory syndrome caused by coronavirus type-2 or SARS-CoV-2. As of 2021, there have been approximately 200 million COVID-19 infections worldwide, resulting in more than 4 million deaths (1). Although many people with COVID-19 infection are asymptomatic or have very mild symptoms, a small number of patients develop severe symptoms and potentially long-term conse- quences. COVID-19 has been linked to more than 50 Effect of SARS-CoV-2 viral infection on male sexual hormones levels post COVID-19 exposure: A systematic review and meta-analysis Anak Agung Patriana Puspaningrat 1, 2, Lukman Hakim 1, 3, Johan Renaldo 1, 3 1 Department of Urology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; 2 Dr. Soetomo General-Academic Hospital, Surabaya, East Java, Indonesia; 3 Universitas Airlangga Teaching Hospital, Surabaya, East Java, Indonesia. DOI: 10.4081/aiua.2024.12113 Summary Archivio Italiano di Urologia e Andrologia 2024; 96(1):12113 A. Agung Patriana Puspaningrat, L. Hakim, J. Renaldo 2 intervention was condition on when admitted for COVID-19 (baseline). The comparison was condition on follow up after COVID. The outcomes were total testos- terone levels, free testosterone, LH and FSH. The inclu- sion criteria for studies were: (1). Observational study, (2). Studies that report the level of total testosterone and at least one of free testosterone, LH, and FSH level at baseline and follow up in patients with SARS CoV-2. Studies that were case reports, conference abstracts, reviews, editorials letters, not available in full text as well as non-English studies were omitted. The systematic search was carried out across PubMed, Scopus, ScienceDirect, Web of Science, and grey literature. The key- words used to search are “COVID”, “SARS-CoV-2”, “COVID-19”, “Corona virus”, “Testosterone level”, “Androgen”, “FSH”, “Follicle Stimulating Hormone”, “LH”, “Luteinizing hormone”, “Free Testosterone”. Quality assessment and data extraction Two authors worked independently to extract data by fill- ing out tabulation templates that had been produced in advance of time. When there are disputes during data extraction, the ultimate choice will be discussed with the senior author. The data obtained comprises study charac- teristics (first author's name, year of publication, sample size, study design, range data col- lection), and basic characteristics of the research sample (age, sever- ity of covid, follow-up range, lab- oratory outcome, and sexual function outcome). The risk of bias was determined using the Newcastle Ottawa Scale (NOS), with a score of 7-9 indicating a low risk of bias, 4-6 suggesting a high risk of bias, and 0-3 indicat- ing a very high risk of bias. Statistical analysis Data analysis was performed using the Review Manager 5.4 software. The outcomes of this study were the level of total testosterone, free testosterone, LH and FSH. Chi- square and I2 tests were used to evaluate heterogeneity between studies. The random-effects model analysis was applied if the heterogeneity test was high (I2 test > 50% and chi-square p < 0.05). If the heterogeneity test was low (I2 < 50%, chi-square p > 0.05), the fixed-effect model analysis was used. The pooled standardized mean and deviation (SMD) with 95% CI were used to perform the analysis on continuous data i.e., testosterone level, free testos- terone, LH and FSH. If there is Median (IQR) or Median (Range) data, it will be converted to Mean ± SD with Median (Range) using scenario 1 and Median (IQR) using scenario 2 from the fol- lowing online calculator https://www.math.hkbu.edu.hk/ ~tongt/papers/median2mean.html. Studies featuring Mean ± SD data that have been stratified by COVID-19 severity will be combined with the following online calculator https://www.statstodo.com/ CombineMeansSDs.php. The results are significant when the P value < 0.05. RESULTS The results of a systematic search for studies using prede- termined keywords identified a total of 606 studies in five databases, namely PubMed/MEDLINE, Scopus, ScienceDirect, Web of science, and grey literature. The num- ber of studies found in each database can be seen in Figure 1. All these studies were then checked for duplication, resulting in 287 duplicate studies. Selection was then car- ried out on 319 studies by reading titles and abstracts, as many as 15 articles that met the criteria and selection con- tinued by reading the full text. The result obtained four studies that met the inclusion criteria and were included in the systematic review of meta-analysis. The four cohort studies revealed a total of 356 COVID-19 patients (6-9). These studies are carried out in a variety of nations, including Italy, Turkey, Russia, and Iran. The first study was conducted in February 2020. At the time of the study, Figure 1. PRISMA diagram of the study search and selection process. Archivio Italiano di Urologia e Andrologia 2024; 96(1):12113 3 SARS-CoV-2 on male sexual hormones participants ranged in age from 34 to 57 years old. The reported follow-up time spans from one month to seven months. Tables 1 and 2 indicate the features of the stud- ies. Newcastle Ottawa Scale was used to measure the qual- ity of the studies. Table 3 shows the quality assessment results, which found three studies with a total score of 8 and one studies with a total score of 7 that were considered to have low risk of bias. Mean total testosterone level Analysis of four studies reporting testos- terone level on COVID-19 showed a signifi- cant difference between total testosterone level on baseline and after following up (pooled SMD = -158.71; 95% CI = -205.30 - -112.12; p < 0.00001) (6-9). The total testos- terone level appears to be lower at baseline. The forest plot for total testosterone level is provided in Figure 2. Mean free testosterone level Analysis of two studies reporting free testosterone level on Table 3. Quality assessment of the study New Ottawa-Scale (NOS). Author (year) Study design Selection Comparability Outcome Total Salonia et al., 2022 Cohort *** ** *** 8 Enikeev et al., 2022 Cohort *** ** *** 8 Apaydin et al., 2022 Cohort *** ** *** 8 Afshari et al., 2022 Cohort *** ** ** 7 Figure 2. Forest plot of mean total testosterone level. Table 1. Basic characteristics of the study. No. Author (year) Data Country Design N Covid Follow-up Age (years) Laboratory Sexual Function collection severity Mean ± SD Outcome Outcome 1. Salonia et al. (2022) (6) February 29 - May 2, 2020 Italy Cohort 121 NR 7 months 57 ± 12 WBC, neutrophils, lymphocytes, NLR, NR creatinine, CRP, IL-6, FSH, LH, tT 2. Apaydin et al. (2022) (7) April - October 2020 Turkey Cohort 29 NR 6 months 43.3 ± 28.6 FSH, LH, tT, fT, Bioavailable testosterone, NR SHBG, lymphocyte, thrombocyte, creatinine, ALT, KDH, ferritin, D-dimer 3. Enikeev et al. (2022) (8) NR Russia Prospective 44 NR 3 months 46.7±9.9 Testosterone, prolactin, LH, FSH IIEF-5 4. Afshari et al. (2022) (9) July 2020 - February 2021 Iran Prospective 162 Severe, moderate 1 month 39.88 ± 7.04 LH, FSH, tT, fT NR Total sample size 356 NR: Not reported; tT: Total testosterone; fT: Free testosterone; WBC: White Blood Cell; NLR: Neutrophil Lymphocyte Ratio; SHBG: Sex Hormone Binding Globulin; ALT: Alanine Aminotransferase; LDH: Lactate Dehydrogenase; IL-6: Interleukin-6; CRP: C-reactive protein; IIEF-5: The International Index of Erectile Function 5. Table 2. Characteristic of study Outcomes. No. Author (year) Data Group N Total testosterone Free testosterone LH FSH IIEF collection (ng/dL) (ng/dL) (mIU/L) (mIU/L) 1. Salonia et al. (2022) (6) February 29 - May 2, 2020 Baseline 121 86 ± 76 NR 5 ± 2.1 6.01 ± 3.37 NR Follow-up 7 months 121 289.28 ± 144.21 NR 4.3 ± 2.25 8.2 ± 3.9 NR 2. Apaydin et al. (2022) (7) April - October 2020 Baseline 29 273.25 ± 175.8 7.74 ± 5.32 9.06 ± 7.77 9.06 ± 7.77 NR Follow-up 6 months 29 349.5 ± 164.5 7.18 ± 2.8 11.1 ± 14.6 5.01 ± 2.44 NR 3. Enikeev et al. (2022) (8) NR Baseline 44 210.54 ± 77.87 NR 3.3 ± 0.5 5.1 ± 1.11 20.7 ± 5.3 Follow-up 3 months 37 395.13 ± 129.84 NR 2.975 ± 0.76 5.05 ± 1.32 23.1 ± 4.3 4. Afshari et al. (2022) (9) July 2020 - February 2021 Baseline 162 124 ± 84 5.14 ± 2.94 7.02 ± 4.83 4.08 ± 2.16 NR Follow-up 1 month 69 259 ± 111 4.76 ± 2.19 6.55 ± 5.48 5.89 ± 3.4 NR Total Sample Size Baseline 356 Follow-up 256 NR: Not reported. Archivio Italiano di Urologia e Andrologia 2024; 96(1):12113 A. Agung Patriana Puspaningrat, L. Hakim, J. Renaldo 4 COVID-19 showed no significant difference between free testosterone level on baseline and after following up (pooled SMD = 0.40; 95% CI = -0.26-1.05; p = 0.24) (7, 9). The for- est plot for testosterone level is provided in Figure 3. Mean luteinizing hormone level Analysis of four studies reporting LH level on COVID-19 showed a significant difference between LH level on base- line and after following up (pooled SMD = 0.40; 95% CI = 0.15-0.65; p = 0.002) (6-9). The forest plot for LH level is provided in Figure 4. Mean follicle stimulating hormone level Analysis of four studies reporting FSH level on COVID- 19 showed no significant difference between FSH level on baseline and after following up (pooled SMD: -0.49; 95% CI = -2.10-1.12; p = 0.55) (6-9). The forest plot for LH level is provided in Figure 5. DISCUSSION This study is the first systematic review and meta-analy- sis to compare male sexual hormone levels in patients with COVID-19 when the SARS-CoV-19 virus was first detected and at follow-up after a negative COVID-19 PCR swab. Four studies were meta-analyzed with a total base- line sample of 356 patients and 256 patients at follow-up with reported follow-up times ranged from 1 month to 7 months. The parameters studied were total testosterone, free testosterone, Luteinizing Hormone (LH), and Follicle Stimulating Hormone (FSH) levels as Mean ± SD. ACE-2 receptors are abundant in testicular tissue. As a result, it is hypothesized that SARS-CoV-2 infection may cause testicular tissue injury, which may lead to impaired sexual function and fertility in men. The primary end- point of this study is the change in total testosterone because it is one of the easiest and simplest male sexual hormone parameter measured with good accuracy in most hospital laboratories. Furthermore, the impact of lower testosterone is concerning given the long-term impact of the SARS-CoV-2 virus on decreased libido lev- els and impaired male fertility. Changes in free testos- terone levels, Luteinizing Hormone (LH) levels, and Follicle Stimulating Hormone (FSH) levels were secondary out- comes of this study. The resulting decrease in testos- terone levels may lead to dysregulation of GnRH produc- tion in the hypothalamus followed by abnormal secretion of LH and FSH from the pituitary. These results indicate Figure 3. Forest plot of mean free testosterone level. Figure 4. Forest plot of mean luteinizing hormone level. Figure 5. Forest plot of mean follicle stimulating hormone level. Archivio Italiano di Urologia e Andrologia 2024; 96(1):12113 5 SARS-CoV-2 on male sexual hormones a decrease in peripheral organ function and a compensa- tory increase in central function (29). Total testosterone The four studies meta-analyzed in this study showed sig- nificant differences in total testosterone levels between baseline and follow-up. At follow up, total testosterone levels in individuals with SARS-CoV-2 infection appeared to be higher in relation to the baseline. This study also found that the testosterone levels of patients who served as baseline data in this study were below the normal range. Most (95%) testosterone is pro- duced in the Leydig cells of the testes depending on stim- ulation by LH. Only a small amount (5%) is produced in the adrenal glands. Low testosterone levels can originate from the testes (primary hypogonadism), hypothalamus- pituitary (secondary hypogonadism), or a combination of both, which is mostly found in the aging male population as late onset hypogonadism (30). In patients with COVID- 19, the increase in gonadotropin concentration as a form of central function compensation may be insufficient because SARS-CoV-2 virus infection may also disrupt homeostatic and cause HPG axis feedback failure (29). The influence of testosterone levels in men on COVID-19 prognosis is currently the focus of attention in several research literatures. Suppressive effects on the gonadal axis through inflammatory mediators, decreased testicu- lar response to gonadotropins, and increased metabolic clearance rate of testosterone have been described as potential causes of lower testosterone concentrations dur- ing acute illness due to the SARS-CoV-2 virus (31). Total testosterone levels can be a prognostic factor of dis- ease severity as low testosterone levels are associated with a high risk of intensive care unit admission and death (10). When there is a decrease in total testosterone levels, the probability of death increases significantly (11). The more severe the comorbidities at the time of treatment, the less likely testosterone levels are to improve over time. In general, testosterone has immunosuppressive effects. Testosterone activates CD8 cells and increases T-helper 1 responses while decreasing natural killer cell responses by decreasing TNF-α and increasing anti-inflammatory IL-10 production (13). Therefore, a poor prognosis in COVID- 19 patients with low testosterone is predictable. However, the Salar et al. study found no significant difference between testosterone levels before the disease in the mild and moderate COVID-19 groups. Possible reasons for this are that severe symptomatic cases were previously exclud- ed and the low number of patients in the study (12). The gradual recovery of total testosterone levels also indi- cated progressive recovery from the severe multisystemic symptoms associated with COVID-19 (10). The study by Xu H et al. also found improvements in testosterone lev- els that can even reach the normal range during recovery from COVID-19 (14). The recovery of physiological testosterone levels can occur as lymphocyte and neu- trophil homeostasis returns, this is also related to old age factors, with or without comorbidities that may affect the ability of some COVID-19 patients to restore testosterone production (13). Thus, the discovery of an upward trend in testosterone levels at follow-up suggests the effect of this decrease in testosterone levels is reversible. Free testosterone The meta-analysis of the two studies in this study did not find any significant changes in baseline and follow-up free testosterone levels. This could be due to the number of studies that could be meta-analyzed only 2 studies with a small sample size and did not include all degrees of COVID-19. Free testosterone levels are decreased in COVID-19 patients. Some studies found a significant association between free testosterone levels and the risk of ICU care or death. Together with total testosterone, free testosterone levels were significantly associated with higher serum levels of LDH, ferritin, procalcitonin, as well as increased neu- trophil levels and decreased lymphocyte counts. Such inflammatory biomarkers are poor prognostic factors for SARS-CoV-2 infection (15). In the Van Zeggeren et al. study, free testosterone levels were significantly lower in patients with severe COVID-19 and in patients who died from severe COVID-19 compared to those who survived. SHBG levels were also associated with the outcome of patients treated with COVID-19 (16). Like total circulating testos- terone, free testosterone levels were significantly decreased in severe patients compared to the mild-moderate group (13). SHBG levels are also associated with the outcome of patients treated with COVID-19 Hypoalbuminemia occurs due to increased vascular permeability and capil- lary leakage is common in critically ill patients and simi- lar mechanisms can lead to low albumin, or CBG con- centrations (16). In addition, serum levels of SHBG, the most widely circulated testosterone-binding protein, showed a significant association with older age in mild- moderate patients, but not in severe patients (13). With age, SHBG levels also increase, causing a decrease in bioavailable testosterone and free testosterone, which affects androgenic activity (20). In COVID-19 patients, SHBG levels were also found to be elevated (30). Thus, in some cases, a decrease in testosterone levels can be caused by an increase in SHBG levels. It takes a decrease in bioavailable testosterone levels or a significant increase in SHBG levels to produce a significant decrease in free testosterone levels (30). Luteinizing Hormone and Follicle Stimulating Hormone This meta-analysis study conducted on 4 studies found significant changes in LH levels between baseline and fol- low-up. There was a decrease in LH levels at follow-up. A possible mechanism is that the SARS-CoV-2 virus enters cells through the ACE-2 receptor which is found in many testicular Leydig cells that regulate testosterone through the conversion of Angiotensin II to Angiotensin 1-7 increasing LH levels (7). Elevated serum LH levels indi- cate primary hypogonadism and testicular failure, rather than secondary causes so this condition is more likely to be influenced by a severe inflammatory state (32). When the inflammatory condition improves characterized by the return of lymphocyte and neutrophil homeostasis, accompanied by the restoration of physiological testos- terone levels, according to the negative feedback mecha- nism of the HPG axis, there will be a decrease in LH and FSH levels (13). However, FSH levels were found to be insignificant. These inconsistent results may be due to the small number of samples, the follow-up time of each Archivio Italiano di Urologia e Andrologia 2024; 96(1):12113 A. Agung Patriana Puspaningrat, L. Hakim, J. Renaldo 6 study and the varying age ranges of research subjects and the varying degrees of severity of COVID-19. In their study, Salar et al. also found no significant difference between FSH or LH hormone levels before and after exposure to COVID-19 in mild or moderate degree groups (12). This could be due to previous exclusion of cases with severe symptoms and the low number of patients in the study (12). The elevated levels of circulating LH and FSH reported in COVID-19 cases may indicate transient activation of GnRH due to the initial inflammatory response (3). This compensatory process by LH against decreased testos- terone levels is also significantly higher in COVID-19 patients compared to healthy men (21). High luteinizing hormone indicates loss of peripheral organ function and compensatory increase in central function (19). SARS- CoV-2 virus has been shown to alter the hypothalamic- pituitary-testis axis, increasing LH and FSH levels in men by suppressing the HPG axis. According to Cayan et al.'s study, blood concentrations of LH and FSH increased with the severity of COVID-19. FSH levels were found to be significantly higher in the ICU group compared to the asymptomatic group (11). In addition to direct damage to the testes by the virus, other factors such as fever, inflammation, and dysregula- tion of the HPG axis may also play a role in testosterone secretion or sperm production (19). Hypothalamic and pituitary tissues also express ACE-2 receptors and there- fore could be targets of the SARS-CoV-2 virus. Low testosterone with normal or low gonadotropins may be caused by the combined effects of COVID-19 on the hypothalamus-pituitary-testis axis and on the testes 7, (13). In addition, emotional, physical, or psychological stress and pain associated with infection may affect the hypothalamic-pituitary axis causing abnormalities in the rhythm of LH secretion (19). COVID-19 treatment Medications given to COVID-19 patients in the general ward or ICU can alter sexual hormone levels such as cor- ticosteroids, anticoagulant drugs, and antiviral drugs such as Remdesivir (26). Animal studies have found that antiviral drugs such as ribavirin (the treatment of choice for COVID-19) can induce oxidative stress, lower testos- terone levels, and severely impair spermatogenesis (4). A considerable decrease in sperm count was observed upon ribavirin treatment. In addition, sperm DNA fragmenta- tion was found up to 8 months even after discontinuation of such treatment. Glucocorticoid treatment is also given to patients who must be admitted to the ICU, potentially affecting testos- terone levels (7). Corticosteroid use and stress-induced hypercortisolism may have a suppressive impact on the hypothalamic-pituitary-Forest plot of mean follicle stim- ulating hormone levelgonadal axis. Corticosteroids can suppress gonadotropin-releasing hormone in the hypo- thalamus and may affect the action of pituitary gonadotropin on the testes (27). Post COVID-19 hypogonadism The results of the Paoli et al. study show that overall andrological health does not appear to be compromised at 3 months after COVID-19 recovery. After a full sper- matogenetic cycle of 3 months there was recovery of semen parameters and sperm DNA fragmentation. This suggests no significant long-term impairment and no sperm autoimmune response. Likewise, the hormone profiles of total testosterone, FSH, and LH showed no rel- evant changes. Ultrasound examination also showed no damage to the testicular parenchyma. These findings reinforce the hypothesis that once clinical recovery occurs, the SARS-CoV-2 virus does not appear to cause direct damage to testicular function, while the impact of indirect damage appears to be transient (28). In the study of Xu et al. using more than 50 days as the cutoff for defining long-term positive cases, Authors found no sig- nificant relationship between testosterone levels and the severity of COVID-19. This means that although the dis- ease course of these patients is longer, the tissues and organs, especially the testes, can still maintain normal conditions or can return to normal. This may be due to the low virulence, achieved immunity, and adequate compensatory capacity to cope with the long-term impact of the virus (14). Circulating testosterone levels were also found to continue to increase over time in men recover- ing from COVID-19. However, nearly 30% of men still showed low testosterone levels even after 12 months dur- ing the recovery period (10). Based on observations, this study is the first systematic review and meta-analysis to compare male sexual hor- mone levels in COVID-19 survivors when the SARS-CoV- 19 virus was first detected and at follow-up. This study can also be the basis for rationalizing the provision of testosterone replacement therapy in cases of acute hypog- onadism which has the possibility of being reversible in male COVID-19 survivors. Currently, there is no direct evidence to confirm that SARS-CoV-2 causes testicular injury leading to hypogonadism and infertility, but the potential risk cannot be ignored. This study has several limitations. Most of the studies had varying follow-up times, many patients were lost to follow-up, most studies did not include the severity of COVID-19, as well as other presence of factors that may affect hormone levels, such as age, comorbidities, psychological conditions, use of medications such as antivirals, corticosteroids, and gluco- corticoids. CONCLUSIONS There was a significant differentiation in total testosterone levels between the initial COVID-19 and the follow-up. Total testosterone levels in individuals with SARS-CoV-2 infection appeared to be higher relative to the baseline, implying that testosterone would return once the COVID-19 infection is resolved, while LH was lower dur- ing follow-up period. 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Correspondence Anak Agung Patriana Puspaningrat patriana.ptty@yahoo.com Department of Urology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General-Academic Hospital, Surabaya, East Java, Indonesia Lukman Hakim lukman-h@fk.unair.ac.id Department of Urology, Faculty of Medicine, Universitas Airlangga, Universitas Airlangga Teaching Hospital, Surabaya, East Java, Indonesia Johan Renaldo (Corresponding Author) joeurologi@gmail.com Department of Urology, Faculty of Medicine, Airlangga University, Soetomo General Academic Hospital Jl. Mayjen Prof. Dr. Moestopo No.6-8, Surabaya, East Java, Indonesia, 60286 Conflict of interest: The authors declare no potential conflict of interest.