Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(2):13645 1 REVIEW among men, with a retrieved 1.6 million cases reported annually worldwide. PCa is recognized as the second most diagnosed malignancy and is the fifth leading cause of death attributed to cancer (1, 2). Several risk factors, including familial predisposition, ethnicity, aging, obesi- ty, and dietary habits, influence PCa (3). While ethnic and racial disparities influence PCa risk, Northern Europe exhibits the highest rates of incidents (83.4 per 100.000) and mortality (13 per 100.000), while South Central Asia has a comparatively lower risk with incidents (6.3 per 100.000) and mortality at (3.1 per 100.000) (4). The prevalence of PCa exhibits significant geographical variations, mostly attributed to disparities in dietary pat- terns. Essential nutrients, encompassing fats, proteins, carbohydrates, vitamins, and polyphenols, may influence the onset and advancement of PCa (5). Mirza et al. demonstrated that certain fruits, including dates, have the potential to induce apoptosis in the human prostate can- cer cell line (PC3). This highlights the potential of certain fruits, which are rich in natural compounds, to exhibit strong anticancer properties (6). At diagnosis, about 80% to 90% of PCa cases are andro- gen-dependent, which underpins the use of androgen dep- rivation therapy (ADT) as the primary treatment (7). The increasing prevalence of PCa and the limited treatment options available necessitate the exploration of novel sup- plementation and preventative strategies for the disease. Chemoprevention is an approach that uses naturally occurring substances found in fruits and vegetables to slow disease progression or even prevent cancer develop- ment (6). Flavonoids are essential chemical components in plants, especially in fruits and vegetables. They are divided into six main subclasses: flavones, flavan-3-ols, flavanones, flavonols, anthocyanidins, and isoflavones (8). Various studies propose that these flavonoids may potentially benefit cancer therapy significantly (9). Flavonoids have also been found to reduce the development of the cell Introduction and objectives: Prostate cancer (PCa) is a significant concern and burden worldwide. Several studies suggest that flavonoids have a signifi- cant potential as an anti-cancer agent, but the evidence remains controversial. This study aims to assess the effect of flavonoids and its subclasses supplementation on PCa risk parameters in men with biopsy-proven diagnosis of PCa or clinically deter- mined to have a high risk of PCa. Materials and methods: This systematic review and meta-analy- sis adhered to PRISMA guideline. A literature search was con- ducted across PubMed, ScienceDirect, Scopus and Cochrane uti- lizing PICO framework. Revised Cochrane’s risk of bias tools (RoB2) was used for quality analysis. Review manager 5.4 was used for statistical analysis. Results: Out of 1.117 articles, nine final studies (involving 420 patients) were included. Regarding total PSA, flavonoid provided a reduction of total PSA (MD: -0.64, p < 0.05), and sub-group analysis based on the supplementation duration showed flavonoid administration with a duration of ≥ 12 weeks signifi- cantly reduced total PSA compared to administration of < 12 weeks (p < 0.05). Meta-analyses of four studies, including men clinically at risk of PCa, revealed that flavonoid supplementation was associated with a significantly lower risk of developing PCa at endpoint (OR 0.41, p < 0.05). However, our results indicated no favorable effect in hormonal parameters. Conclusions: The results of this meta-analysis suggest there may be a potential role for flavonoid in PCa risk reduction. Flavonoids supplementation also have been proven to be safe. However, further investigation is necessary to gain a clear understanding of the flavonoid impact on PSA and sex hormone parameters. Key wORDS: Prostate cancer; Oncology; Flavonoids; Meta-analysis. Submitted 18 January 2025; Accepted 1 February 2025 INTRODUCTION Prostate cancer (PCa) represents a significant global health issue, being a primary contributor to illness and death The effect of flavonoid and subclasses supplementation on prostate specific antigen (PSA), hormonal parameters and prostate cancer risk: A systematic review and meta-analysis of randomized controlled trials Abdul Azis 1, 2, Andi Asadul Islam 2, 3, Haerani Rasyid 2, 4, Lukman Hakim 5, Syakib Bakri 2, 4, Agussalim Bukhari 2, 6, Andi Alfian Zainuddin 7 1 Urology Division of Surgery Department, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia; 2 Hasanuddin University Teaching Hospital, Makassar, Indonesia; 3 Neurosurgery Divison of Surgery Department, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia; 4 Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia; 5 Department of Urology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 6 Department of Nutritional Sciences, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia; 7 Department of Public Health and Community Medicine, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia. DOI: 10.4081/aiua.2025.13645 Summary Archivio Italiano di Urologia e Andrologia 2025; 97(2):13645 A. Azis, A. Asadul Islam, H. Rasyid, et al. 2 cycle, cause apoptosis, and inhibit metastasis, invasion, and angiogenesis (10). Although many studies have been published, the connec- tion between flavonoids and PCa remains debated. This study conducted a meta-analysis to explore the effects of flavonoid supplementation and its subclasses on men diag- nosed with PCa or considered high-risk, focusing on criti- cal factors influencing PCa development and progression. METHODS Literature search On April 1, 2024, a literature study was conducted by three reviewers across multiple databases, including PubMed, ScienceDirect, Scopus and Cochrane Library. The search utilized keywords ‘Prostate AND Cancer AND flavonoid OR flavonol OR flavone OR flavanone OR fla- van-3-ol OR isoflavone. This study applied no restrictions regarding country or publication year. The protocol of this meta-analysis was registered in PROSPERO (CRD42024615073). eligibility criteria The systematic review followed the PICO framework with the following eligibility criteria: (1) the study included participants diagnosed with prostate cancer (PCa) or clas- sified as high-risk due to clinical indicators; (2) interven- tion using rich-food or purified flavonoid and its sub- classes; (3) comparing with placebo; (4) outcome includ- ing PSA parameters, hormonal parameters (testosterone, estradiol and Sex Hormone Binding Globulin (SHBG), developing biopsy-detectable PCa and reporting adverse events; (5) randomized controlled study; (6) published in Indonesian or English. Selection process After the initial search, duplicate studies were identified and excluded. At least three independent reviewers screened the remaining studies for eligibility based on their titles and abstracts. Studies that fulfilled the prede- termined inclusion criteria were incorporated into the analysis, whereas those that did not meet these criteria were excluded. Discrepancies regarding study classifica- tion were addressed through collective discussion among the research team. The literature review process adhered to the PRISMA guidelines (11). Data collection Data collection was performed independently by each author, with cross-checking by others to address any inconsistencies through discussion. If any information was unclear, the study authors were contacted for clarifi- cation, and studies with no response were excluded with the consent of the other reviewers. The data gathered included the first name of author, year, study design, population characteristics, mean age, type of interven- tion, control type, reported outcomes, and adverse events from all included studies. Quality analysis Revised Cochrane Risk of Bias tool (RoB2) was used for quality analysis, with each study being assigned a risk of bias rating of low, high, or some concerns at each evalu- ation point. Publication bias Publication bias was evaluated with a funnel plot analy- sis. Publication bias considered to be high if the distribu- tion of studies was asymmetrical. Conversely, if the study distribution was evenly distributed and symmetrical, publication bias was considered to be low. Statistical analysis Meta-analyses were conducted to evaluate the impact of flavonoids or their subclasses on PCa risk, comparing them to a placebo in Review Manager 5.4. The first meta- analyses assessing the effect between groups in PSA parameters and hormonal parameters were performed by entering the mean ± SD to measure the mean difference (95% CI) and were sub-grouped by effect of duration (< 12 weeks or ≥ 12 weeks) if the data was sufficient. The second meta-analysis was performed by entering the inci- dence of biopsy-detectable PCa in populations clinically determined as having PCa risk to measure the odds ratio (95% CI) between groups. The heterogeneity of the sta- tistical analysis was evaluated by the I2 value. The fixed- effects model was employed when I² was less than 50%, whereas the random-effects model was utilized when I² was equal to or greater than 50%. The findings were illus- trated through a forest plot, and an overall effect was deemed statistically significant if the p-value was less than 0.05 (12). RESULTS Literary search and examination results A total of 1.117 studies were initially identified from var- ious databases. The studies included in this analysis were published prior to April 1, 2024. After removing 125 duplicates, two reviewers independently screened the remaining 1.052 study by titles and abstracts. Of these, 1.043 studies were excluded for failing to meet the eligi- bility criteria. As a result, nine studies were deemed eligi- ble and included in the qualitative and quantitative analy- sis. A detailed overview of the search and filtering results is presented in Figure 1. Characteristics of eligible studies The nine studies were RCTs done in various countries, involving a cumulative sample size of 420 participants including 186 men with PCa biopsy-proven diagnosis and Gleason score ≥ 6 in four studies (13-16), 218 men at ele- vated risk of PCa (elevated PSA, ASAP, HGPIN or negative prostate biopsy) in four studies (17-20) and 16 men with a history of radical prostatectomy less than 3 years before with elevated PSA (≥ 0.1 ng/ml) in one study (21). In all studies flavonoid or its subclasses in various form were given, eight studies used a purified isoflavone rich-food (14-16, 19-21) or isoflavone supplement in capsule or tablet (13, 18), only one study (17) used a Flavan-3-ols subclass of flavonoid with PolyE capsule containing Epigallocatechin gallate (EGCG). In all trials most controls Archivio Italiano di Urologia e Andrologia 2025; 97(2):13645 3 Flavonoid effect on PSA, hormonal parameters and prostate cancer risk used placebo. Most studies used 12 weeks or more as an end-point outcome, only two studies had < 12 weeks inter- vention duration (13, 16). The outcomes assessed total PSA in six studies (13, 15-17, 19, 21) and free PSA in three studies (15, 16, 19), as well as hormonal parameters, which consist of total testosterone observed in four studies (13, 15, 16, 20), free testosterone in four studies (13-15, 20), total estradiol in four studies (13-15, 20) and SHBG in five studies (13, 15, 17, 18, 20). Additionally, three studies (17, 18, 20) provided data on the incidence of PCa at the end of intervention of men clin- ically at risk of PCa. Only four studies (13, 14, 17, 18) have reported data on the flavonoid intervention side effects, with the majority reporting a small sample size of 1-2 grade side effects. Full details regarding the details of studies are presented in Table 1. Study quality results The risk of bias assessment results indicated that all stud- ies generally had a low risk of bias. However, one study raised some concerns regarding its overall risk, as shown in Figure 2. Publication Bias results Funnel plot results of studies on Total PSA (Supplementary Figure 1A) and SHBG (Supplementary Figure 2D) showed an asymmetrical distribution. The other results of the stud- ies showed a symmetrical distribution as shown in Supplementary Figures. Therefore, it can be concluded that the results of this analysis have a low risk of publica- tion bias. Statistical analysis (Meta-analysis) PSA parameters There were two outcomes in the assessment of PSA param- eters: total PSA and free PSA. The result of the forest plot revealed that in the comparison between flavonoid supple- mentation and placebo, there was a significant difference in total PSA (MD: -0.64, p < 0.05). Sub-group analysis based on the supplementation duration showed that flavonoid administration with a duration of ≥ 12 weeks significantly reduced total PSA compared to administration of ≤ 12 weeks (p < 0.05). However, no significant statistical differ- ence was revealed for free PSA (MD: 0, p = 0.99). Figure 3 shows the detailed forest plot of PSA parameters. Figure 1. Flow of literature search and selection based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Archivio Italiano di Urologia e Andrologia 2025; 97(2):13645 A. Azis, A. Asadul Islam, H. Rasyid, et al. 4 Figure 2. Risk of bias assessment using the revised Cochrane risk-of-bias tool algorithm for randomized trials (RoB 2.0). ASAP: Atypical Small Acinar Proliferation; CI: Confidence Interval; EGCG: Epigallocatechin gallate; PCa: Prostate Cancer; PIN: Prostatic Intraepithelial Neoplasia; PSA: Prostate Specific Antigen; RCT: Randomized Controlled Trial; SHBG: Sex Hormone Binding Globulin. Table 1. Baseline characteristics data of included studies. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13645 5 Flavonoid effect on PSA, hormonal parameters and prostate cancer risk Hormonal parameters There were four outcomes in the assessment of hormon- al parameters. The total testosterone forest plot revealed a difference between groups in total testosterone (MD: 1.49, p < 0.05) and free testosterone (MD: -0.47, p < 0.05). There was no statistical significance regarding total estradiol (MD: 0.61, p = 0.38) and SHBG (MD: -0.02, p = 0.99). Figure 4 shows the detailed forest plot of hor- monal parameters. Prostate cancer risk There were four included studies dealing with a popula- tion of men clinically at risk of PCa that reported data on the incidence of PCa biopsy-proven diagnosis at the end of intervention. The forest plot revealed that the group of patients who received flavonoid supplementation was associated with a markedly reduced risk of developing PCa (OR 0.41, p < 0.05). The estimated analysis associat- ed with the incidence of PCa is presented in Figure 5. DISCUSSION The objective of this study was to evaluate the findings from RCTs regarding the impact of flavonoids and their various subclasses in male individuals diagnosed with PCa or those classified as at risk for developing PCa. This sys- tematic review included nine RCTs in total. Four studies recruited men with biopsy-proven diagnosis of PCa, four studies included men who were considered to have a risk of PCa and one study included men with a history of rad- ical prostatectomy with elevated PSA. Our findings sug- gest that flavonoid consumption may lower total PSA serum levels and reduce the incidence of PCa. A subgroup analysis revealed that flavonoid supplementation for more than 12 weeks significantly reduced the risk of PCa. While previous meta-analyses found no link between flavonoid intake and PCa risk, the limitations of these studies may have influenced their conclusions. Notably, all the studies included in that meta-analysis were obser- vational studies. The amounts of flavonoid consumption CI: Confidence interval; IV: Inverse variance; SD: Standard deviation. Figure 3. Forest plots of PSA parameter: (A) Total PSA sub-group based on the duration of intervention (< 12 weeks or ≥ 12 weeks). (B) Free PSA. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13645 A. Azis, A. Asadul Islam, H. Rasyid, et al. 6 Figure 4. Forest plots of hormonal parameter: (A) Total testosterone sub-group based on the duration of intervention (< 12 weeks or ≥ 12 weeks). (B) Free testosterone. (C) Total estradiol. (D) Sex hormone binding globulin (SHBG). CI: Confidence interval; IV: Inverse variance; SD: Standard deviation. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13645 7 Flavonoid effect on PSA, hormonal parameters and prostate cancer risk were derived from self-reported data provided by the par- ticipants, without a standardized method of categoriza- tion. Additionally, the research participants were catego- rized based on their various levels of flavonoid consump- tion, and the author was unable to evaluate the impact of higher flavonoid intake on the risk of PCa (22). Flavonoids are a major category of dietary polyphenols that are found naturally in plant-based food, including fruits, vegetables, tea, and wine. Dietary products have a well-documented historical precedent as preventive agents in the fight against various forms of cancer. Natural substances such as green tea, grape skin, pome- granate, dates, and soy are known for their chemo-pre- ventive properties. Scientific evidence strongly supports that consuming diets rich in plant-based foods may sig- nificantly lower the chance of developing many types of cancer. The precise mechanism via which these foods provide protection against the formation of tumours and the development of cancer is not yet understood. However, one possibility is that they may contain phyto- chemicals with potential anticancer properties (23). In addition, according to laboratory research conducted on fruits such as dates, which are rich in flavonoids, it has been shown that they can induce apoptosis in the PC3 cells of the human body. Flavonoids are suggested to have the ability to trigger apoptosis in tumour cells, which might potentially have a preventive impact against PCa (6). Researchers have identified PSA as a biomarker for the initial detection and prognosis of PCa. Prostatic luminal epithelial cells produce it and it plays a role in regulating semen coagulation. PSA is thought to be elevated due to cellular architecture disruptions, and it circulates in both free and complex forms (24). Reports indicate that some flavonoids have the ability to prevent the production of PSA by the BT-454 cell line. This may explain the notable correlation between consumption of flavonoids and a reduced risk of PCa (25). Our findings indicated a statis- tically significant difference in total PSA (MD: -0.64, p < 0.05) between study groups. A sub-group analysis based on the length of supplementation showed that giving flavonoids for more than 12 weeks significantly decreased total PSA compared to giving them for less than 12 weeks (p < 0.05). However, free PSA showed no significant sta- tistical difference (p = 0.99). The results of our meta-analyses showed that there were no significant impacts on sex hormone levels. The results align with a 2013 meta-analysis of researches on isoflavones, which concluded that there was no signifi- cant influence on reproductive hormones in individuals with PCa (26). In contrast, a research investigation on the administration of soy isoflavone supplements at a dosage of 60 mg per day resulted in a reduction in testosterone and 5α-dihydrotestosterone (DHT) levels, while simultane- ously increasing SHBG levels in a group of healthy males aged 30 to 59 years (27). These data do not provide a clear understanding of the impact of sex hormone levels. Looking at each of these, the pooled results of several small studies showed no significant changes. In line with a previous meta-analysis by Van Die et al., which examined the cancer risk in men clinically deter- mined to be at risk (including those with a single negative prostate biopsy at the start of a 12-month study or those with ASAP or HGPIN over a 6-month period), it was found that soy isoflavones significantly reduced the like- lihood of developing PCa. This conclusion was support- ed by a statistically significant analysis (RR = 0.49, p < 0.05) (26). In our analysis, four studies were included, focusing on men clinically at risk of PCa. The forest plot analysis showed that individuals who received flavonoid supplementation exhibited a markedly lower risk of developing PCa (OR = 0.41, p < 0.05). These findings suggest a significant association between flavonoid intake and a lower risk of PCa. Testosterone and DHT work through the androgen recep- tor to control cell proliferation and differentiation. Androgens play a pivotal role in the normal development of the prostate gland, but they also contribute to the pro- liferation of prostate tumors, which is the primary target of androgen deprivation therapy (ADT). The implementa- tion of ADT is associated with various side effects that can significantly impact both the quality of life and overall health of patients. Certain dietary supplements may pro- vide benefits for persons undergoing ADT. Research has shown that flavonoids, such as phytoestrogen, have the ability to mitigate certain adverse effects linked to ADT. Research conducted by Durreger et al. found that dietary treatments including certain natural compounds might be beneficial in the adverse effects associated with ADT (7). Our study also demonstrated the safety of flavonoid sup- Figure 5. Forest plot of studies about subjects who had a risk of developing prostate cancer (PCa) becoming biopsy-detectable PCa at the endpoint. CI: Confidence interval; IV: Inverse variance; SD: Standard deviation. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13645 A. Azis, A. Asadul Islam, H. Rasyid, et al. 8 plementation and its potential for use in PCa patients undergoing ADT. It is important to address some limitations in our study. First, out of all the interventions available, only the flavonoid subclass isoflavone and flavan-3-ols were avail- able from our included studies due to the limited number of published articles. This implies that our included study does not provide an analysis of other subclasses of flavonoids. Second, our inclusion studies have a relative- ly small overall sample size. Furthermore, the examina- tion of some results revealed significant heterogeneity, which is to be expected considering the variability in the impact of flavonoids depending on the length of supple- mentation. Consequently, dividing into subgroups based on 12-week periods decreased the heterogeneity. CONCLUSIONS The findings of this study indicate that flavonoids and their respective subclasses may contribute to the reduc- tion of PCa risk. Flavonoid supplementation is effective in lowering total PSA levels, particularly when administered for ≥ 12 weeks. Additionally, flavonoids appear to reduce the risk of PCa incidence in populations clinically identi- fied as high-risk. Flavonoid supplementation has also been shown to be safe. Nonetheless, additional investiga- tions are warranted to determine the optimal dose and duration of flavonoid supplementation. REFERENCES 1. Tzelepi V. Prostate Cancer: Pathophysiology, Pathology and Therapy. Cancers. 2022; 15:281. 2. Rawla P. Epidemiology of Prostate Cancer. World J Oncol. 2019; 10:63-89. 3. Sekhoacha M, Riet K, Motloung P, et al. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Mol Basel Switz. 2022; 27:5730. 4. Giona S. The Epidemiology of Prostate Cancer. 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Availability of data and material: All data and materials from this research are available to the researcher and we will provide it upon request if the researcher needs it. Competing interests: The authors certify that there is no con- flict of interest with any financial organization regarding the material discussed in the manuscript. Funding: All funding for this research comes from researchers without receiving research costs or research grants from third parties. Authors' contributions: Contribution Details AA ASA HR LH SB AB AAZ Concepts √ √ √ √ √ √ √ Design √ √ √ √ √ √ √ Definition of √ √ √ intellectual content Literature search √ √ √ Data acquisition √ √ √ √ √ Data analysis √ √ √ Statistical analysis √ √ √ Manuscript preparation √ √ √ √ √ Manuscript editing √ √ √ Manuscript review √ √ √ √ √ √ √ Guarantor √ √ √ √ √ √ √ Acknowledgments: We as authors would like to thank all parties involved in this study, including the Department of Urology, Faculty of Medicine, Hasanuddin University and also Hasanuddin University Hospital. Conference Presentation: This article has not been present- ed at any conference. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13645 9 Flavonoid effect on PSA, hormonal parameters and prostate cancer risk prevention study: an investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen. Cancer Sci. 2012; 103:125-130. 19. 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Correspondence Abdul Azis (Corresponding Author) abdul.azis031@gmail.com Perintis Kemerdekaan St. KM. 10, Tamalanrea, Makassar, Indonesia (Postal Code: 90245) Andi Asadul Islam undee@med.unhas.ac.id Haerani Rasyid haeranirasyid@med.unhas.ac.id Lukman Hakim lukman-h@fk.unair.ac.id Syakib Bakri syakibbakri@yahoo.com Agussalim Bukhari agussalim.bukhari@med.unhas.ac.id Andi Alfian Zainuddin a.alfian@med.unhas.ac.id