Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(3):14332 1 ORIGINAL PAPER INTRODUCTION Benign prostatic hyperplasia (BPH) is a prevalent, nonma- lignant condition characterized by the proliferation of prostatic stromal and epithelial cells, typically occurring in aging males. This hyperplastic growth may contribute to lower urinary tract obstruction and the development of lower urinary tract symptoms (LUTS), which negatively affect patients' quality of life and functional status (1). In addition, chronic prostatic inflammation has been impli- cated in the progression of BPH and is associated with increased prostate volume and symptom severity (2, 3). Pharmacologic management of BPH primarily includes α1-adrenergic receptor antagonists and 5α-reductase inhibitors. However, these agents frequently cause adverse effects such as orthostatic hypotension, reduced libido, and ejaculatory dysfunction, which can impair adherence and limit long-term utility (1, 4). Accordingly, there is increasing clinical interest in nutraceuticals and plant-derived therapies that may offer symptomatic relief with a more favorable side-effect profile. Xipag® is a dietary supplement composed of pollen extract and teupolioside - a polyphenolic glycoside extracted from Ajuga reptans that exhibits 5α-reductase inhibitory activi- ty, potentially modulating androgenic signaling in prostat- ic tissue (5). Pollen extract, rich in phytosterols and anti- inflammatory compounds, may enhance therapeutic out- comes through its antioxidative, anti-inflammatory, and muscle-relaxant properties (6). This study aimed to evaluate the clinical efficacy of Xipag® in men with BPH, with primary endpoints focused on sex- ual function, ejaculatory function, quality of life (QoL), and patient global impression of improvement (PGI-I). Secondary endpoints included urodynamic parameters and LUTS symptom reduction. METHODS This prospective, single-arm observational study was conducted in accordance with the ethical standards of the Declaration of Helsinki and was approved by the institu- Background: Benign prostatic hyperplasia (BPH) is a common age-related condition that often results in lower urinary tract symptoms (LUTS), reduced quality of life, and sexual dysfunction. Conventional pharmacotherapies, while effective, are frequently associated with adverse effects on sexual and ejaculatory function. This study evaluated the sexual safety and clinical efficacy of a dietary supplement containing pollen extract and teupolioside, in men with BPH. Methods: In this prospective, single-arm observational study, 25 men with moderate LUTS due to BPH received daily pollen extract and teupolioside supplementation for 90 days. The pri- mary endpoints were sexual function (International Index of Erectile Function, IIEF-5), ejaculatory function (Male Sexual Health Questionnaire–Ejaculatory Dysfunction, MSHQ-EjD), quality of life (IPSS-QoL), and patient global impression of improvement (PGI-I). Secondary endpoints included changes in urinary flow (Qmax) and LUTS severity (International Prostate Symptom Score, IPSS). Assessments were conducted at base- line, 1 month, and 3 months. Results: Sexual and ejaculatory functions remained stable over the treatment period, with no statistically significant deteriora- tion observed. QoL improved significantly by the 3-month mark (IPSS-QoL median score reduced from 3 to 2; p < 0.008), and PGI-I scores reflected high patient satisfaction (median 2, IQR 1). Qmax significantly increased from 12.4 mL/s at baseline to 15.5 mL/s at 3 months (p < 0.001), and IPSS scores significant- ly declined from 11 to 8 (p < 0.008), indicating improved uri- nary function. Conclusions: The pollen extract and teupolioside supplementa- tion was well tolerated and associated with improved QoL and urinary outcomes, without compromising sexual or ejaculatory function. These findings support its potential as a non-pharma- cologic adjunct in the management of BPH, particularly in patients concerned about sexual side effects. Further random- ized controlled studies are warranted to confirm these results. KEY WORDS: Benign prostatic hyperplasia; Teupolioside; Nutraceutical; Sexual safety; Lower urinary tract symptoms. Submitted 6 September 2025; Accepted 12 September 2025 Sexual safety and efficacy of a pollen extract and teupolioside-based supplement in men with benign prostatic hyperplasia: A prospective observational study Matteo Vittori 1, 2*, Valerio Iacovelli 1, 2*, Marco Carilli 1, 2, Carlo Brocca 3, Michele Antonucci 1, 2, Filomena Petta 1, 2, Beatrice Filippi 1, Giulia Di Giovanni 1, Marta Signoretti 1, 2, Francesco Maiorino 1, 2, Andrea Benedetto Galosi 3, Pierluigi Bove 1, 2 1 Urology Unit, San Carlo di Nancy General Hospital - GVM Care and Research, Rome, Italy; 2 Minimally Invasive and Robotic Urology Unit, Tor Vergata University of Rome, Rome, Italy; 3 Urology Unit, Azienda Ospedaliero-Universitaria delle Marche, Polytechnic University of Marche, Ancona, Italy. * These authors contributed equally to this work and share first authorship. DOI: 10.4081/aiua.2025.14332 Summary Archivio Italiano di Urologia e Andrologia 2025; 97(3):14332 M. Vittori, V. Iacovelli, M. Carilli, et al. 2 tional Ethics Committee (STS CE Lazio1/N-945, “Lazio 1”, San Camillo Forlanini Hospital, Rome, Italy). Written informed consent was obtained from all participants. A total of 25 male patients with BPH-associated LUTS were enrolled. Inclusion criteria comprised age ≥ 18 years, serum prostate-specific antigen (PSA) ≤ 4 ng/mL, prostate volume ≤ 60 mL, Qmax ≤ 15 mL/s, and post-void residual (PVR) volume < 150 mL. Patients were excluded if they had urinary tract infection, urological malignancy, prior prostate surgery, significant comorbidities (e.g., neurogenic bladder, uncontrolled diabetes), or hypersen- sitivity to the supplement's components. Eligible participants received a daily regimen of Xipag® (IDI Integratori Dietetici Italiani S.r.l., Aci Bonaccorsi, CT, Italy), administered as one tablet per day over a 90-day period. Each daily dose of Xipag® , contained the following active compounds: pollen extract (Graminex® G96®; 500 mg) and teupolioside (Teupol 25P; 60 mg). No additional pharmaco- logical treatments targeting BPH were prescribed during the study period to avoid confounding effects. At baseline (T0), patients signed informed consent, underwent clinical evaluation, uroflowmetry, ultrasono- graphic evaluation of PVR. Patient-reported outcomes measures (PROMs) were evaluat- ed using validated symptom and QoL questionnaires. Evaluations were conducted at baseline (T0), 1 month (T1), and 3 months (T2, end of treatment). Primary out- comes were assessed using: International Index of Erectile Function (IIEF-5), Male Sexual Health Questionnaire- Ejaculatory Dysfunction (MSHQ-EjD), IPSS-QoL domain, Patient Global Impression of Improvement (PGI-I). Secondary outcomes included uroflowmetry (Qmax) and the International Prostate Symptom Score (IPSS). In this study, artificial intelligence (AI), specifically ChatGPT (chatgpt.com), was used solely for reviewing the English language in its grammar, syntax, and style, with- out affecting content, citations, or interpretative and con- clusive discussions. Statistical analysis Continuous variables were summarized using medians and interquartile ranges (IQRs). The Wilcoxon signed- rank test was used to compare scores at T0, T1, and T2. A p-value < 0.05 was considered statistically significant. RESULTS A total of 25 patients completed the study protocol. Baseline characteristics of study population were the fol- lowing: median age 55 years (interquartile range, IQR 14); median prostate volume 44 ml (IQR 15); median PSA 1.4 ng/ml (IQR 1.5). PROMs and functional results during follow-up are summarized in Table 1. Among the primary endpoints, sexual function, as meas- ured by the International Index of Erectile Function (IIEF- 5), showed no significant changes across time points. The median score was 21 (IQR: 3) at both baseline and 1 month (p = 0.5), with a slight increase to 22 (IQR: 4) at 3 months (p = 0.08). Ejaculatory function, evaluated through the MSHQ-EjD function domain, demonstrated stable median values: 13 (IQR: 3) at baseline, 12 (IQR: 2) at 1 month (p = 0.8), and 12 (IQR: 3) at 3 months (p = 0.4), indicating no signifi- cant change. The MSHQ-EjD bother domain remained unchanged between baseline and 1 month with a median of 1 (IQR: 3; p = 0.7) and decreased slightly to 0 (IQR: 2) at 3 months, though not reaching statistical significance (p = 0.08). Quality of life (QoL), assessed via the IPSS-QoL domain, remained stable at 1 month with a median of 3 (IQR: 1) compared to baseline (3, IQR: 2; p = 0.8), but improved significantly at the 3-month follow-up to a median of 2 (IQR: 1; p < 0.008). A critical component of patient-cen- tered care, the Patient Global Impression of Improvement (PGI-I), confirmed the subjective benefit reported by patients. At the 3-month evaluation, the median PGI-I score was 2 (IQR: 1), denoting that most patients per- ceived their condition as “much improved” or “very much improved”. Importantly, more than half of the participants (52%) expressed a desire to continue the treatment beyond the study period, indicating high patient satisfac- tion and acceptability of the supplement. Regarding the secondary endpoints, a progressive and ultimately statistically significant enhancement in urody- Table 1. Baseline characteristics and results of questionnaires and functional outcomes during follow-up. N = 25 Baseline 1-month P-value * 3-months P-value ** IIEF, median (IQR) 21 (3) 21 (3) 0.5 22 (4) 0.08 MSHQ-EjD ejaculatory function domain, median (IQR) 13 (3) 12 (2) 0.8 12 (3) 0.4 EJ-MSHQ bother item, median (IQR) 1 (3) 1 (3) 0.7 0 (2) 0.08 Qmax, median (IQR) 12.4 (4.6) 13.5 (7.6) 0.1 15.5 (4) < 0.001 PVR (ml), median (IQR) 15 (20) 12.5 (20) 0.1 12.5 (25) < 0.01 IPSS (LUTS domain), median (IQR) 11 (4) 10 (8) 0.4 8 (2) < 0.008 IPSS-QoL (QoL domain), median (IQR) 3 (2) 3 (1) 0.8 2 (1) < 0.008 PGI-I 2 (1) * p-value between 1-month follow-up and baseline. ** p-value between 3-months and baseline follow-up. IIEF International Index of Erectile Function (IIEF-5); IPSS: International Prostate Symptom Score; IPSS-QoL: International Prostate Symptom Score-Quality of Life; Male Sexual Health Questionnaire–Ejaculatory Dysfunction (MSHQ-EjD); PGI-I: Patient Global Impression of Improvement; PVR: Post-void residual; PVR: Post-void residual volume. Archivio Italiano di Urologia e Andrologia 2025; 97(3):14332 3 Pollen extract and teupolioside-based supplement in men with BPH namic parameters was observed. At baseline, the median maximum urinary flow rate (Qmax) was 12.4 ml/s (IQR: 4.6). An increase to 13.5 ml/s (IQR: 7.6) was observed at 1 month, though this change was not statistically signifi- cant (p = 0.1). At 3 months, Qmax significantly improved to 15.5 ml/s (IQR: 4), with a p-value < 0.001, indicating a clinically relevant improvement in urinary flow (Figure 1). The International Prostate Symptom Score (IPSS) for LUTS showed a median baseline value of 11 (IQR: 4), which slightly decreased to 10 (IQR: 8) at 1 month (p = 0.4). A significant reduction was noted at 3 months, with a medi- an score of 8 (IQR: 2) (p < 0.008), reflecting symptom alleviation over time. DISCUSSION The findings of this study offer preliminary yet com- pelling evidence supporting the clinical utility of Xipag® – a dietary supplement composed of pollen extract and teupolioside – in the management of BPH, particularly in patients presenting with moderate LUTS and a preserved sexual function profile. Crucially, our analysis demonstrated that the supplement had a favorable effect on the primary outcomes of sexual function, ejaculatory function, QoL, and PGI-I. Although sexual function and ejaculatory parameters did not exhibit statistically significant changes, they remained stable throughout the study period. The IIEF-5 showed no sig- nificant variation: median values remained 21 (IQR: 3) at baseline and T1 (p = 0.5), with a non-significant increase to 22 (IQR: 4) at T2 (p = 0.08). This suggests that the sup- plement neither impaired nor meaningfully enhanced erec- tile function. Similarly, ejaculatory function assessed by the MSHQ-EjD function domain, remained unchanged, with median scores of 13 (IQR: 3) at baseline, 12 (IQR: 2) at T1 (p = 0.8), and 12 (IQR: 3) at T2 (p = 0.4). The MSHQ-EjD bother domain showed a mild, non-significant decline in bother scores from a median of 1 (IQR: 3) at baseline and T1 to 0 (IQR: 2) at T2 (p = 0.08). This is particularly rele- vant in the context of BPH treatment, where commonly prescribed drugs such as α1-blockers and 5α-reductase inhibitors are known to impair sexual performance and ejaculatory function. The preservation of sexual health seen with Xipag® is thus not merely a neutral finding, but a comparative advantage that may enhance treatment adher- ence and patient satisfaction. The observed non-significant upward trend in IIEF-5 scores at 3 months suggests a pos- sible mild benefit that warrants further investigation in a larger cohort. Perhaps the most notable result in this domain was the sig- nificant enhancement in QoL, as evidenced by the IPSS- QoL score at the 3-month mark. QoL scores remained unchanged at 1 month (median 3, IQR: 1; p = 0.8), but improved significantly at 3 months (median 2, IQR: 1; p < 0.008). This improvement paralleled a substantial propor- tion of patients reporting subjective symptom relief via the PGI-I, indicating a concordance between objective ques- tionnaire data and patient experience - an essential aspect of any therapeutic intervention, particularly for chronic and quality-of-life-limiting conditions such as BPH. In terms of secondary endpoints, the supplement pro- duced significant improvements in both objective and subjective urological measures. The Qmax showed a statis- tically and clinically meaningful increase by the end of the Figure 1. Uroflowmetry (y = Qmax) in the 25 patients (x = patients). The blue line represents baseline flow characteristics; the green line represents the median trend of the traces at the end of the 90-day treatment period. Archivio Italiano di Urologia e Andrologia 2025; 97(3):14332 M. Vittori, V. Iacovelli, M. Carilli, et al. 4 study, suggesting a reduction in urinary tract obstruction or improvement in bladder emptying. The Qmax demon- strated a progressive improvement over time. At baseline, the median Qmax was 12.4 ml/s (IQR: 4.6), increasing to 13.5 ml/s (IQR: 7.6) at T1. Although the early increase did not achieve statistical significance (p = 0.1), a signifi- cant enhancement was observed at T2, with Qmax reach- ing 15.5 ml/s (IQR: 4) (p < 0.001). From a baseline medi- an score of 11 (IQR: 4), IPSS decreased to 10 (IQR: 8) at T1 (p = 0.4), and significantly declined to 8 (IQR: 2) at T2 (p < 0.008) indicating that symptom relief may accrue with continued administration - potentially reflecting the gradual anti-inflammatory and anti-androgenic effects of the supplement’s active components. The mechanism of action of Xipag® appears to be multi- factorial. Teupolioside has demonstrated inhibitory effects on 5α-reductase, potentially decreasing intrapro- static dihydrotestosterone levels and thereby reducing prostatic volume and obstruction. This pathway is analo- gous to that targeted by finasteride or dutasteride, but without the hormonal side effects that frequently accom- pany those medications. In parallel, pollen extract offers a rich profile of phytosterols, flavonoids, and essential fatty acids, contributing antioxidative and anti-inflamma- tory properties, along with smooth muscle relaxation. Together, these mechanisms provide a plausible pharma- cological basis for the observed improvements in urinary flow and symptom burden, as well as the absence of detri- mental effects on sexual function. These findings are broadly consistent with prior literature, including clinical studies by Lo Re et al. (7) and Muraca et al. (8), which evaluated the same fixed-dose combination. Both studies reported reductions in IPSS scores and enhancements in QoL, alongside excellent tolerability and patient adherence. Our study reinforces these conclusions while further emphasizing the sexual safety profile of the supplement - a domain that remains underrepresented in BPH supplement research. Nevertheless, a number of limitations must be acknowl- edged. The sample size was relatively small (n = 25), lim- iting statistical power and generalizability. The lack of a control group – placebo or otherwise – precludes defini- tive causal inference, and the single-arm design intro- duces potential for performance, observer, and expecta- tion bias. Additionally, the 3-month duration, while suf- ficient to demonstrate initial therapeutic effects, does not provide insight into long-term efficacy, sustainability of benefit, or potential delayed adverse events. These con- cerns are particularly relevant given the chronic nature of BPH, which often requires extended treatment timelines. Despite these constraints, the absence of adverse events, in combination with significant improvements in QoL, uri- nary function, and patient-reported outcomes, positions Xipag® as a viable non-pharmacologic adjunct or alterna- tive in the therapeutic landscape of BPH. Importantly, its use may be especially advantageous in patients who are unwilling or unable to tolerate conventional medications due to side effects, particularly those related to sexual function. Moving forward, these preliminary findings underscore the need for randomized, double-blind, placebo-con- trolled trials involving larger patient cohorts and longer follow-up durations. Such studies should incorporate not only symptom scores and urodynamic parameters but also objective biomarkers of inflammation, prostate vol- ume changes, and detailed sexual function domains. Stratification by baseline sexual function status and symptom severity could also help delineate which sub- groups stand to benefit most from Xipag® therapy. CONCLUSIONS In this preliminary investigation, Xipag® demonstrated promising efficacy in improving QoL and patient-report- ed outcomes in men with BPH, without compromising sexual or ejaculatory function. Secondary benefits includ- ed improved urinary flow and reduced LUTS severity. These findings support the potential role of Xipag® as a non-pharmacologic adjunct or alternative in BPH man- agement. Further controlled studies are necessary to establish its long-term safety and therapeutic value. REFERENCES 1. Cornu, JN, Gacci M, Hashim H, et al. EAU Guidelines on Non Neurogenic Male Lower Urinary Tract Symptoms (LUTS). European Association of Urology. Last updated April 23, 2025. 2. Gandaglia G, Briganti A, Gontero P, et al. The role of chronic pro- static inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). BJU Int. 2013; 112:432-41. DECLARATIONS Ethical approval and consent for participate: This prospec- tive, single-arm observational study was conducted in accordance with the ethical standards of the Declaration of Helsinki and was approved by the institutional Ethics Committee (STS CE Lazio1/N-945, “Lazio 1”, San Camillo Forlanini Hospital, Rome, Italy). Written informed consent was obtained from all partici- pants. Availability of data and material: The data that support the findings of this study are available from the corresponding author, [VI], upon reasonable request. 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: The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. Authors' contributions:Matteo Vittori conceived the study, con- ducted the literature review and collected the data; Valerio Iacovelli conceived the study, wrote the manuscript; Marco Carilli conceived the study, wrote the manuscript; Carlo Brocca reviewed the manuscript; Filomena Petta collected the data, interpreted the results; Beatrice Filippi performed the statistical analysis; Giulia Di Giovanni performed the statistical analysis; Marta Signoretti collected the data; Francesco Maiorino collected the data; Michele Antonucci collected the data; Andrea Benedetto Galosi reviewed and edited; Pierluigi Bove conceived the study, wrote the manu- script, reviewed and edited. Acknowledgments: None. Archivio Italiano di Urologia e Andrologia 2025; 97(3):14332 5 Pollen extract and teupolioside-based supplement in men with BPH 3. Fusco F, Creta M, De Nunzio C, et al. 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Discovering a new nutraceutical based on pollen extract and teupolioside: a prospective monocentric study evaluating its role in alleviating lower urinary tract symptoms in benign prostatic hyperplasia patients. Arch Ital Urol Androl. 2025; 97:13412. 8. Muraca L, Scuteri A, Burdino E, et al. Effectiveness and Safety of a New Nutrient Fixed Combination Containing Pollen Extract Plus Teupolioside, in the Management of LUTS in Patients with Benign Prostatic Hypertrophy: A Pilot Study. Life (Basel). 2022; 12:965. Correspondence Matteo Vittori matteo.vittori@ptvonline.it Valerio Iacovelli (Corresponding Author) Valerio.iacovelli85@gmail.com Marco Carilli marco.carilli@ptvonline.it Carlo Brocca brocca.carlo@gmail.com Michele Antonucci michele.antonucci@ptvonline.it Filomena Petta filomena.petta@ptvonline.it Marta Signoretti marta.signoretti@ptvonline.it Francesco Maiorino francesco.maiorino@ptvonline.it Pierluigi Bove pierluigi.bove@ptvonline.it Policlinico Tor Vergata, Unità di Urologia Robotica e Mininvasiva, Viale Oxford 31, 00133, Rome, Italy Beatrice Filippi beatrice.filippi87@gmail.com Giulia Di Giovanni giuliadigiovanni28@gmail.com Urology Unit, San Carlo di Nancy General Hospital - GVM Care and Research, Rome, Italy Andrea Benedetto Galosi andreabenedetto.galosi@ospedaliriuniti.marche.it Urology Unit, Azienda Ospedaliero-Universitaria delle Marche, Polytechnic University of Marche, Ancona, Italy