Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(1):13318 1 REVIEW INTRODUCTION Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms (LUTS) in men due to bladder outlet obstruction (1). Symptoms range from increased urinary hesitancy, urgency, and frequency to acute urinary retention. Histologic BPH is found in approx- imately 50% of men aged 50 years, and its prevalence increases about 10% each subsequent decade (2). Likewise, significant LUTS are documented to occur in about 10%- 20% of men aged 50-59 and increase to one-third of men by ages 70-79. In parallel, prostate volume increases between age 40 and age 79, with the greatest increases appearing in the sixth and seventh decades of life (3). Recent studies have uncovered several genes linked to both BPH and prostate cancer. For instance, Li et al. (4) investigated the V89L and A49T SRDA52 polymorphisms, while Zhang et al. expanded the search by examining geno- type distributions of SRD5A2, CYP17, CYP19, and VDR genes in Chinese populations (4, 5). Additionally, Choubey et al. (5) focused on polymorphisms at the (TA)n locus. Together, these investigations, alongside others exploring correlations across diverse populations, significantly enhanced our understanding of the genetic factors that may impact the development of BPH and prostate cancer. Previous researchers have noted the presence of alleles with low catabolic activity including two polymorphic sites: an alanine to threonine substitution at codon 49 (A49T) and a valine to leucine substitution at codon 89 (V89L) (6). The V89L polymorphism correlates with reduced concentra- tions of androstanediol glucuronide, free testosterone, and testosterone (7). Individuals with the “LL” genotype exhib- it a slight, nonsignificant, decrease in androstanediol glu- curonide concentrations compared to those with the “VV” genotype. The L allele's moderate reduction in SRD5A2 activity results in lower dihydrotestosterone (DHT) levels, although the biological mechanism behind this genotype's connection with decreased DHT production remains unclear (4). However, DHT levels in the prostate are influ- enced by various factors, including testosterone metabo- lism and DHT inactivation. Testosterone, not DHT, appears to be the primary androgen promoting prostate Introduction and objectives: Being the most common disease in aged men, the etiology of Benign Prostatic Hyperplasia (BPH) is not fully defined. Recent studies have reported that the association between Benign Prostate Hyperplasia and metabolic genes is still incon- sistent. A gene connected with BPH is SRD5AR2, whose polymor- phisms, A49T and V89L, have distinct enzyme activity. This systematic review examines SRD5AR2 polymorphisms within two alleles (A49T and V89L), assessing their roles as prognostic indicators of malignancy, and response to medication. Materials and methods: We conducted a search on six different databases, including PubMed, Scopus, Wiley, ProQuest, Cochrane Central, and Science Direct using as string of key- words (BPH) AND [(rs523349) OR (V89L)] AND [(rs9282858) OR (A49T)]. We finally selected seven articles to be extracted. Quality appraisal of clinical trials was evaluated using the Joanna Briggs Institute Approach for systematic reviews. Results: We sorted nine clinical studies from various countries examining SRDA52 polymorphism and its association of BPH and prostate cancer. About V89L we found that the "LL" geno- type, indicating reduced 5α-reductase activity, is linked to a lower BPH risk, while the "VV" genotype may slightly increase BPH risk. About A49T, compared to “AA” genotype, “AT” tends to be associated to higher risk in developing prostate cancer. A49T polymorphism does not show any effect on medical treat- ment while V89L showed a protective effect on the clinical pro- gression of BPH when treated with 5a-reductase inhibitors, a- adrenergic receptor antagonists, and alpha blockers. Conclusions: SRD5A2 polymorphisms could be a good indicator for prognostic malignancy and a potential tool for personalized medicine of BPH. The findings strongly support the recommen- dation for further study about SRD5AR2 to enhance its use for screening and prevention and to optimize the medical treat- ment of Benign Prostatic Hyperplasia. KEY WORDS: Benign prostatic hyperplasia; Prostate cancer; Genetic polymorphism; Prognosis; Personalized medicine. Submitted 30 October 2024; Accepted 5 December 2024 A comprehensive systematic review of studies on the potential of A49T and V89L polymorphism in SRD5AR2 as high susceptibility gene association with benign prostate hyperplasia and prostate cancer Revina Maharani 1, Hotma Lestari 1, Putra Mahakarya Dewa 1, Dewangga Yudisthira 1, Nasim Amar 1, Besut Daryanto 2 1 Medical Faculty, Universitas Brawijaya, Malang, Indonesia; 2 Urology Department, Faculty of Medicine Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, Indonesia. DOI: 10.4081/aiua.2025.13318 Summary Archivio Italiano di Urologia e Andrologia 2025; 97(1):13318 R. Maharani, H. Lestari, P. Mahakarya Dewa, et al. 2 carcinogenesis (8). In addition to the V89L polymorphism, the SRD5A2 A49T is linked to a significantly lower con- centration of androstanediol glucuronide, indicating its impact on androgen metabolism (9). The SRD5A2 poly- morphism likely represents a crucial point in DHT metab- olism, possibly explaining its association with prostate can- cer risk. This underscores the complexity of genetic factors influencing prostate cancer susceptibility. Both polymor- phisms likely contribute to variations in androgen levels, potentially influencing prostate cancer development (10). To the best of our knowledge, there has been limited research about A49T and V89L polymorphisms of SRD5AR2 as BPH risk factor. Considering the role in benign prostatic hyperplasia and in the risk of malignan- cy and in their treatment, the Authors were interested in reviewing evidence about SRD5AR2 polymorphisms A49T and V89L, in order to assess their roles as prognos- tic indicators for malignancy and response to medication. MATERIALS AND METHODS Data sources and search strategy The systematic review was carried out based on the Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) guidelines by utilizing the PubMed, Scopus, Wiley, ProQuest, Cochrane Central, and Science Direct. Article search for papers in English was done using boolean operators with the following keywords: [(Benign Prostatic Hyperplasia) OR (BPH) OR (Prostate Cancer)] AND [(rs523349 OR V89L) AND (rs9282858 OR A49T)]. The inclusion criteria were: case-control or cohort study; study investigating gene polymorphisms A49T and V89L in SRD5AR2 and their association with BPH and prostate cancer; written in English. Quality appraisal of clinical tri- als was evaluated using the Joanna Briggs Institute Approach for systematic reviews. Selection process The authors individually evaluated findings of literature search, beginning with the titles and abstracts of papers which passed eligibility criteria screening. Any disagreement was freely discussed with one senior author to settle them. The entire text was then examined to weed out research that were not relevant. Data extraction The selected articles were extracted by the Authors, who then assessed their suitability. Disagreements were dis- cussed and ultimately settled after each author reviewed the articles on his own. Name of the author, year of publi- cation, country, study design, number of samples, sample characteristics, intervention, comparison, length of follow- up, and desired outcomes were taken from eligible studies. RESULTS Study selection After the literature search, 116 articles were retrieved by the six databases. Several articles were excluded due to duplication of studies (n = 29). Some papers were exclud- ed because they did not adhere to inclusion criteria (n = 36). There were 41 articles excluded due to ineligible data, such as review articles and books, and inaccessible articles due to subscriptions. Finally, nine articles were included in the systematic review to be analysed qualita- tively and quantitatively. Figure 1 shows the PRISMA flowchart. Study design This review consists of 9 clinical studies with varying designs: 1 cross-sectional, 3 case-control, 2 cohort stud- ies, and 3 clinical trials. The total number of participants across all studies includes 1,226 individuals, comprising prostate cancer patients, BPH patients, and healthy con- trols. Methods of diagnosis and assessment included blood diagnostic criteria, prostate-specific antigen (PSA) testing, digital rectal examination (DRE), and biopsy results. The geographic distribution of the studies includes Bulgaria, China, Japan, the USA, India, and Sweden. The review emphasizes the impact of gene poly- morphism and its associations with prostate diseases, explores and discusses their implications for personalized medicine. Risk of bias summary The risk of bias for various study designs; case-control, cohort, and cross-sectional was evaluated using the JBI Critical Appraisal Tools. According to the risk of bias assessment, three studies were found to have a moderate risk of bias, primarily due to ambiguous statements in areas such as the identification of confounding factors and the strategies used to address them, as well as incom- plete data throughout the studies. The remaining studies (n = 6) were classified as having a low risk of bias (see Figure 2). Despite the varying levels of bias across the included studies, most of the data have been thoroughly examined and discussed. The reviewers concluded that, overall, the studies are sufficiently suitable for analysis. Study result summary Gene polymorphism Results for V89L variant of SRD5A2 are reported in Table 1. For the A49T, men with the AT/TT genotypes were at increased risk for BPH, asymptomatic, and symptomatic BPH and prostate cancer compared to men with the AA genotype, although none of the OR reached statistical sig- nificance. Association to malignancy Based on the studies on V89L polymorphism that were evaluated, it was shown that “LL” allele, that confers a low activity of 5 alpha reductase, was less common in patients with prostate cancer. On the other hand, “VV” locus, which is commonly found in the Hispanic population, is associated with a higher risk of BPH. The A49T gene consists of “AA” locus and “TT” locus pro- ducing “AA”, “AT”, and “TT” genotypes. All of the geno- types mentioned have no statistically significant correla- tion to malignancy, although “AT” and “TT” genotypes have a higher risk of developing prostate cancer. “AT” Archivio Italiano di Urologia e Andrologia 2025; 97(1):13318 3 SRD5AR2 gene association with benign prostate hyperplasia and prostate cancer Figure 1. PRISMA flowchart of the literature selection. Figure 2. Risk of bias assessment Archivio Italiano di Urologia e Andrologia 2025; 97(1):13318 R. Maharani, H. Lestari, P. Mahakarya Dewa, et al. 4 variants were more frequently found among Prostate Cancer patients while “AA” variants were least likely to be found on patients with prostate cancer and BPH. Response to drugs Both genes demonstrated a protective effect against the clinical progression of BPH when treated with 5α-reduc- tase inhibitors, α-adrenergic receptor antagonists, and alpha blockers. Populations with the “LL” genotype were likely more suitable to have a standard or herbal treat- ment for BPH. DISCUSSION The results of the present study, when contextualized with previous research (11-16), provide a deeper under- standing of the role of genetic polymorphisms in the SRD5A2 gene, particularly V89L and A49T, in the devel- opment and progression of prostate pathological condi- tions like BPH and prostate cancer (PCa). The associations between these polymorphisms and disease risk highlight the genetic mechanisms that may influence prostate enlargement and malignancy, as well as the potential for personalized treatment strategies based on these genetic markers. Our findings on the V89L polymorphism align with pre- vious studies showing that the SRD5A2 gene encoding an enzyme responsible for converting testosterone into dihy- drotestosterone (DHT), plays a key role in prostate growth. The activity of this enzyme also known as 5-alpha reduc- tase type 2 is linked to the severity of BPH. The V89L polymorphism shows distinct enzyme activity variations that influence androgen levels and drive prostate growth, potentially leading to prostate cancer. Our review found that the "LL" genotype is less common in prostate cancer patients, suggesting that this allele may have a protective effect by lowering 5-alpha reductase activity and, consequently, DHT production. Table 1. Gene polymorphism. Archivio Italiano di Urologia e Andrologia 2025; 97(1):13318 5 SRD5AR2 gene association with benign prostate hyperplasia and prostate cancer Table 2. Prognostic to Malignancy Archivio Italiano di Urologia e Andrologia 2025; 97(1):13318 R. Maharani, H. Lestari, P. Mahakarya Dewa, et al. 6 These results are consistent with a study by Konwar et al. (17), which reported that the LL genotype is associated with lower androstanediol glucuronide concentrations, thereby reducing free testosterone and DHT levels. This may explain the reduced prostate volume and lower cancer risk in individuals with the "LL" genotype com- pared to those with the "VV" genotype. Furthermore, the higher risk of BPH associated with the "VV" allele was also supported by Lunn et al. (18) research, which indicated ethnic differences in V89L polymorphism prevalence. In Asian populations, such as those in India and Japan, the polymorphism was found at higher rates, contribut- Table 3. Response to medical treatment. Archivio Italiano di Urologia e Andrologia 2025; 97(1):13318 7 SRD5AR2 gene association with benign prostate hyperplasia and prostate cancer ing to an increased risk of BPH. This suggests that the genetic impact of the V89L variant may vary across dif- ferent ethnicities, with certain populations exhibiting a higher predisposition to prostate diseases. Regarding the A49T polymorphism, our review found no statistically significant association with malignancy, though the "AT" and "TT" genotypes tended to be associated with a higher risk of developing prostate cancer compared to the "AA" genotype. This aligns with Giwerchman et al. (15), who estimated that the A49T polymorphism could be found in approximately 8% of prostate cancer patients and 6.3% of BPH patients, indicating its role in increasing the probabili- ty of developing BPH and prostate cancer. Although not as prominent in Asian populations, this polymorphism is commonly observed in Hispanic populations, as well as in certain countries like Turkey and China. While the statistical significance of the A49T polymor- phism in relation to malignancy remains inconclusive in our review, these findings emphasize its potential impor- tance as a genetic marker for prostate cancer susceptibil- ity. This warrants further research, especially in non- Hispanic populations, to determine whether the A49T variant can be used as a predictive tool for prostate dis- ease risk in other ethnic groups. The study findings on gene polymorphisms in the SRD5A2 gene also underscore the potential for personal- ized medicine in treating prostate-related conditions. According to Li et al. (14), the SRD5A2 gene regulates critical hormonal pathways, influencing prostate growth and function. This insight into the biochemical pathways driven by V89L and A49T polymorphisms supports the idea of genotype-driven therapeutic approaches. Both V89L and A49T polymorphisms demonstrated pro- tective effects against the clinical progression of BPH when treated with 5-alpha reductase inhibitors and α- adrenergic receptor antagonists. These findings imply that personalized treatment strate- gies based on genetic markers could optimize therapeutic outcomes and reduce the likelihood of disease progres- sion, offering a more tailored approach to managing BPH and prostate cancer. A study by Daryanto et al. (19) showed that combination of dutasteride with tamsulosin could give a more signifi- cant effect in terms of lowering the contractility of prostate smooth muscle. While the findings of this review are compelling, they also reveal the need for further research. The prevalence of V89L and A49T polymorphisms in Hispanic popula- tions has been well-documented, but additional studies in Asian populations are necessary to understand their role in diverse genetic backgrounds. For example, as noted by Lunn et al. (18), the V89L polymorphism shows high prevalence in India and Japan, suggesting a popula- tion-specific effect. Expanding genetic studies to include other Asian regions may yield valuable insights into the global relevance of these polymorphisms. Additionally, larger cohort studies and more diverse pop- ulation sampling are needed to strengthen the associa- tions between these polymorphisms and prostate cancer or BPH risk. A more detailed exploration of the mecha- nistic pathways involved in DHT production and andro- gen activity, particularly in relation to the SRD5A2 gene, will be essential for translating these genetic insights into clinical practice. This study confirms the significant role of the SRD5A2 gene and its V89L and A49T polymorphisms, in influ- encing the risk of prostate disease and its progression. Both variants have distinct effects on the enzyme activity and androgen levels, impacting on prostate growth and the likelihood of developing BPH or prostate cancer. Ethnic differences in polymorphism prevalence further highlight the importance of population-specific genetic research. By integrating genetic profiling into clinical practice, personalized medicine approaches may offer more effective and targeted treatment options for prostate-related conditions, improving patient outcomes while minimizing unnecessary interventions. CONCLUSIONS In conclusion, this systematic review proves that SRD5A2 is a high susceptibility gene that is linked to BPH. A49T and V89L are the polymorphism of the gene involved. ninBoth polymorphism varies in different ethnic popula- tions. Further studies are required to evaluate different risk factors and outcomes after medical treatment in dif- ferent geographical situation in order to provide a better theoretical basis to study the role of genetic in the patho- genesis of BPH and prostate cancer. REFERENCES 1. Roehrborn CG. Benign prostatic hyperplasia: an overview. Rev Urol. 2005; 7(Suppl 9):S3-S14. 2. 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Correspondence Revina Maharani 10maharanirevina@gmail.com Hotma Lestari hotlesmo67@gmail.com Putra Mahakarya Dewa putramahakaryadewa25@gmail.com Dewangga Yudisthira dewanggay369@gmail.com Nasim Amar nasemamar2003@gmail.com Medical Faculty, Universitas Brawijaya, Malang, Indonesia Besut Daryanto (Corresponding Author) urobes.fk@ub.ac.id Urology Department, Faculty of Medicine Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, Indonesia