The use of a single daily dose of tadalafil to treat signs and symptoms of benign prostatic hyperplasia and erectile dysfunction

Efficacy and Safety of 12-week Monotherapy With Once Daily 5 mg Tadalafil for Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia: Evidence-based Analysis

Jianwei Cui † , Dehong Cao † , Yunjin Bai, Jiahao Wang, Shan Yin, Wuran Wei, Yunfei Xiao, Jia Wang * and Qiang Wei *

Background: Tadalafil has been approved for the treatment of benign prostatic hyperplasia (BPH) for nearly 10 years. However, there are insufficient evidence-based studies of the efficacy and safety of tadalafil in treating lower urinary tract symptoms of BPH (LUTS/BPH).

Objective: To evaluate the therapeutic effect and clinical safety of tadalafil monotherapy (5 mg once daily for 12 weeks) for LUTS/BPH.

Methods: A total of 13 studies (15 randomized clinical trials [RCTs]) were extracted from the following databases: PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science for the period up to July 2021. The quality of the included RCTs was evaluated independently by two authors, who, respectively, extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses principles. Conflicts were settled by a discussion with two-third of senior authors. All data analyses were conducted by the Review Manager, version 5.4.

Conclusions: This study demonstrates that once daily 5 mg tadalafil is a potentially effective and safe treatment choice with excellent tolerability for patients with LUTS/BPH.

Systematic Review Registration: Identifier (CRD42021228840).

Introduction

Benign prostatic hyperplasia (BPH), which is caused by the proliferation of epithelial and stromal cells in the transition zone of the prostate, is characteristic of nonmalignant hyperplasia of prostatic tissue and is highly prevalent in older men (1). Lower urinary tract symptoms (LUTS) associated with BPH include storage or irritative (mainly including urinary frequency, urgency, and nocturia), voiding or obstructive (mainly including urinary hesitancy, straining, retention, and a decreased force of urination), and postmicturition symptoms, which can significantly and negatively affect the quality of life (QoL) of the elderly (2, 3). More than 50% of men > 50 years and over 80% of men > 80 years old experience LUTS/BPH (4).

In addition to surgical intervention, alpha-blockers (ABs), 5-alpha reductase inhibitors (5ARIs), and phytotherapies (monotherapy or cotherapy) have been prescribed for the treatment of LUTS related to BPH for decades (5, 6). Although these drug treatments are effective, they can cause troublesome adverse reactions, such as hypotension, dizziness, and sexual dysfunction (7, 8). Tadalafil, one of the phosphodiesterase type 5 inhibitors (PDE5Is) used to improve the symptoms of erectile dysfunction (ED), has been increasingly investigated and gained approval for the treatment of BPH in many countries since 2011 (9).

This is mainly because PDE5Is are believed to likely act mainly by increasing the concentration of nitric oxide (NO), which improves the activity of intracellular cyclic guanosine monophosphate (cGMP) (10). This system is collectively called the NO-cGMP signaling pathway, and its activation could lead to the relaxation of smooth muscle in the detrusor, bladder neck, and prostate (10). In addition, PDE5Is not only ameliorate intraprostatic inflammation-associated BPH but also improve tissue oxygenation and blood supply and thereby playing a vital part in alleviating LUTS (9, 11).

Recent meta-analyses comparing the effect of tamsulosin as a monotherapy and a cotherapy with tadalafil in improving LUTS/BPH, have concluded that cotherapy might be more suitable for patients than monotherapy (12, 13). However, analyses of tadalafil 5 mg monotherapy administered once daily for the treatment of LUTS/BPH are rare. Despite the use of tadalafil monotherapy, LUTS/BPH has been reported to improve significantly following treatment with this strategy (14). Therefore, in this study, we conducted the latest and high-quality synthesis of current worldwide evidence to evaluate the therapeutic effect and clinical safety of tadalafil 5 mg once daily monotherapy for 12 weeks in men with LUTS/BPH.

Materials and Methods

Study Protocol

The study registration application has been submitted to the International Prospective Register of Systematic Reviews (CRD42021228840) and the report was prepared using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Information Sources and Literature Search

A comprehensive and systematic search of PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science databases was performed for the period up to July 2021 by using the following key terms: [(“Prostatic Hyperplasia”[Mesh]) OR (Benign Prostatic Hyperplasia) OR (Hyperplasia, Prostatic) OR (Prostatic Hypertrophy) OR (Adenoma, Prostatic) OR (Adenomas, Prostatic) OR (Prostatic Adenomas) OR (Prostatic Adenoma) OR (Prostatic Hyperplasia, Benign) OR (Prostatic Hypertrophy, Benign) OR (Benign Prostatic Hypertrophy) OR (Hypertrophy, Benign Prostatic) OR (“lower urinary tract symptoms”[Mesh]) OR (lower urinary tract symptom)] AND [(“Tadalafil”[Mesh]) OR (Pyrazino (1′,2′:1,6) pyrido (3,4-b)indole-1,4 -dione,6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-) OR (IC-351) OR (IC 351) OR (Cialis)]. Reference lists of relevant articles were also manually searched and the “related articles” function was used to identify additional articles in PubMed. The subsequent document filtration and data extraction were performed independently by the two authors (JW Cui, DH Cao), and conflicts on suitable articles were settled by discussion and consultation with two-third senior authors (Q Wei, J Wang).

Study Selection

Trials included in our study met the following criteria according to the population, intervention, comparator, outcome, and study design (PICOS) approach: (P) male patients were diagnosed as LUTS/BPH; (I) taking medication: 12-week monotherapy with once daily 5 mg tadalafil; (C) treatment with an oral isodose placebo in the same way; (O) evaluating the following outcomes: changes in the total International Prostate Symptom Score (IPSS), IPSS storage (or irritative) subscore, IPSS voiding (or obstructive) subscore, IPSS quality of life (IPSS QoL), adverse events (AEs), and serious adverse events (SAEs); and (S) randomized controlled trials (RCTs). In addition, we excluded reviews, case reports, meeting abstracts, comments, letters to the editor, and animal research.

Statistical Analysis

The outcome indicators were the QoL affected by LUTS/BPH scored using the IPSS, IPSS storage subscore, IPSS voiding subscore, BPH impact index (BII), IPSS QoL, the maximum flow rate (Q_max), and the postvoid residual (PVR). Furthermore, safety-related findings assessed based on AEs and SAEs were additional indicators. Efficacy was evaluated by analyzing index changes from baseline to 12 weeks, whereas safety was assessed by comparing AE-related data. The analyses were mainly conducted using the Review Manager, version 5.4 (Cochrane Collaboration, Oxford, the UK). Specifically, heterogeneity was evaluated with Cochrane’s Q-statistic test and the I 2 tests. The random-effects model was used when heterogeneity was accepted at a P_Q < 0.10 or I 2 > 50%, otherwise, the fixed-effects model was used. The risk of bias was independently assessed by two authors using the Jadad scale (≥3 scores represented high-quality studies), funnel plot, and the Cochrane Collaboration’s tool for assessing the risk of bias, and conflicts were resolved by reaching a consensus through discussions. Sensitivity analysis was performed in the outcome indicators, respectively, by sequentially excluding each study. To find out more information about the ideal candidate for tadalafil monotherapy, several linear regressions were performed. Continuous variables reported as a mean and SD in the original articles were converted from standard error into SD for this study: SD = standard error * (sample size) 1/2 . A 95% CI was chosen whether mean difference (MD) was used to express the continuous data or risk ratio (RR) was used for dichotomous data.

Result

Search Results and Quality Assessments

A total of 1,425 relevant articles were extracted from the databases through systematical and manual search strategies. Eventually, 13 articles (15–27) involving 9,525 participants were identified, of which 15 trials that met the eligibility criteria were included in this study. While the follow-up period was different in each study, we pooled data of the change from baseline to 12 weeks from the studies.

Figure 1 illustrates the literature search process used and Table 1 shows the mean baseline characteristics. The symmetrical funnel plot roughly revealed no selection biases or no small sample studies with poor methodological quality (Figure 2A). The risk of biases was presented further in the risk of bias graph summary and risk of bias graph, which illustrated that the probability of each bias in every study is quite small (Figure 2B). Apart from Q_max, the rest of the indicators have reached the insubstantial heterogeneity standard (P_Q > 0.10 or I 2 < 50% in forest plots) in Cochrane Reviewers’ Handbook. In addition, no significant differences from the original analysis were found after sensitivity analysis.

Efficacy

Total IPSS

The total IPSS, IPSS voiding subscore, and IPSS storage subscore were reported in all the trails we selected. The data pooled from 15 studies (15–27) including 9,525 participants (4,937 and 4,588 in the tadalafil and placebo groups, respectively), and provided the necessary information for this study. The subsequent analysis result revealed a significantly larger total IPSS change from the baseline to 12 weeks in the tadalafil group (MD: −1.97 95% CI: −2.24 to −1.70, P < 0.00001, Figure 3A) than in the placebo group.

Figure 3. Forest plot of (A) the total IPSS; (B) the IPSS voiding subscore; (C) the IPSS storage subscore; (D) the IPSS QoL; (E) BII; (F) Q_max; and (G) PVR. IPSS, International Prostate Symptom Score; PVR, postvoid residual; QoL, quality of life.

IPSS Voiding Subscore and IPSS Storage Subscore

A total of 15 studies (15–27) included in the analysis recorded the change in the IPSS voiding and storage subscores from baseline to 12 weeks. The analysis of the combined data showed that tadalafil significantly reduced the IPSS voiding and storage subscores more than the placebo did, and the MD of the change in the two subscores was −1.30 (95% CI: −1.48 to −1.11, P < 0.00001, Figure 3B) and −0.70 (95% CI: −0.82 to −0.58, P < 0.00001, Figure 3C), respectively.

The IPSS Quality of Life

A total of 14 studies (15–26) including 9,423 participants (4,886 and 4,537 in the tadalafil and placebo groups, respectively) investigated the IPSS QoL improvement data. The fixed-effects estimate of the MD was −0.29 (95% CI: −0.35 to −0.22, P < 0.00001, Figure 3D).

BPH impact Index

Eight studies (15–18, 21–23) including 3,682 participants (1,852 and 1,830 in the tadalafil and placebo groups, respectively) compared the effect of the treatments on the BII. Overall, the pooled MD was −0.58 (95% CI: −0.76 to −0.40, P < 0.00001, Figure 3E) in the fixed-effect model, which indicated the BII was significantly lower in patients administered tadalafil therapy than in those who received the placebo.

These results suggested that tadalafil oral monotherapy (5 mg once daily for 12 weeks) significantly improved LUTS/BPH in the treated patients. Interestingly, the better improvement in IPSS seemed to be in connection with the younger age, the high BMI, and the high baseline IPSS (Figure 4).

Figure 4. Influence of (A) the baseline of the total International Prostate Symptom Score (IPSS), (B) age, and (C) body mass index on IPSS improvement.

The Maximum Flow Rate (Q_max)

The mean change in the Q_max was calculated from pooled data from seven studies (15, 16, 18–21, 23) including 2,891 participants (1,458 and 1,433 in the tadalafil and placebo groups, respectively). The results showed an insignificant difference between tadalafil and the placebo, with an MD of 0.11 (95% CI: −0.41 to 0.63, P = 0.68, Figure 3F).

Postvoid residual

Five studies (16, 18, 19, 21, 23) including 2,188 participants (1,106 and 1,082 in the tadalafil and placebo groups, respectively), provided information about the change in the PVR from baseline to 12 weeks. The results indicated that the decrease in PVR was similar between these two groups, with an MD of −0.89 (95% CI: −5.53 to 3.76, P = 0.71, Figure 3G).

Safety

In our study, the most common AEs were headache (3.59%), nasopharyngitis (3.21%), dyspepsia (2.92%), and back pain (2.29%). The results of meta-analyses showed that a higher incidence of headache, dyspepsia, and back pain was associated with tadalafil monotherapy (Table 2).

Table 2. Most common reported treatment-related adverse events.

The AEs and SAEs that occurred in the tadalafil and placebo groups were compared in this review. All the studies included (15–27) in the analysis reported the incidence of AEs, which showed a significant difference between the tadalafil and placebo groups with a RR of 1.27 (95% CI: 1.19–1.36, P < 0.00001, Figure 5A). However, the comparison of incidences of SAE did not show any significant difference between the two groups (RR: 1.27, 95% CI: 0.80–2.01, P = 0.31, Figure 5B) in the 13 studies including 8,436 participants (4,393 and 4,043 in the tadalafil and placebo groups, respectively).

Figure 5. Forest plot of (A) AE and (B) SAE. AE, adverse event; SAE, serious adverse event.

Discussion

This systematic review and meta-analysis have demonstrated comprehensively the therapeutic effect and clinical safety of 12-week monotherapy with once daily 5 mg tadalafil for LUTS/BPH. In our study, the total IPSS improvement was clinically meaningful after a tadalafil monotherapy, which significantly improved the IPSS voiding and storage subscores, IPSS QoL, and BII, whereas no statistically significant difference was found in terms of Q_max and PVR. In addition, the result shows that tadalafil and placebo were similar in the matter of the incidence of SAEs, although the difference in AEs was statistically significant.

Medicinal management has become the standard of therapy in patients diagnosed with moderate to severe LUTS/BPH, whereas surgery is performed in those who fail to respond to medication. Tamsulosin is regarded as an effective treatment for LUTS/BPH because it selectively blocks α₁ receptors to induce smooth muscle relaxation in the bladder, neck, and prostate (28). Furthermore, tamsulosin 0.4 mg administered once daily is used in Western countries and is the safest AB in combination with PDE5Is (12). As a recommended medicine, tamsulosin could improve the symptom score by 4–6 points in the European Association of Urology guidelines. Likewise, the total IPSS was reduced by an average of 4.7–6.4 points with tadalafil monotherapy in the studies we included. Coincidentally, the study by Oelke (19), comparing with tamsulosin, monotherapy with tadalafil seemed to be a similar therapeutic effect in improving moderate to severe LUTS/BPH. All these make it necessary to test whether tadalafil is effective in LUTS/BPH with more sufficient evidence.

Tadalafil, the only PDE5I used for the treatment of BPH, was initially prescribed for the treatment of ED in 2003 but later proved to be effective in LUTS/BPH. Consequently, this agent was approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of symptoms of BPH especially when accompanied by ED (29). A dose-finding study was conducted with a sample size of 1,058 patients experiencing LUTS/BPH who were randomly assigned to receive tadalafil (2.5, 5, 10, or 20 mg) or a placebo once daily. The results showed that tadalafil administered at all the tested doses significantly improved the symptoms more than the placebo did, and tadalafil 5 mg daily showed a more positive risk-benefit profile (15). In fact, an oral dose of 5 mg per day is the standard for tadalafil (12). Dong et al. (30) performed a meta-analysis of studies reporting the use of monotherapy for LUTS in 2012, whereas Wang et al. (31) conducted a similar study in 2016. However, the tadalafil dose used in the included trials in the article by Dong et al. (30) was not unified in the analysis of the comprehensive effect of four different doses, and the number of studies included was small in the latter passage (30, 31). Furthermore, three related literature reports (25–27) (four RCTs) have been published over the last 5 years. Therefore, the latest and largest pooled analysis and systematic review are urgently required to evaluate the therapeutic effect and clinical safety of tadalafil with a unified dose (5 mg once daily) and a uniform endpoint (12 weeks) in patients with LUTS/BPH.

The reduced indexes, including the total IPSS, IPSS voiding and storage subscores, IPSS QoL, and BII, showed the relief of symptoms of BPH and the improvement of QoL. As we all know, IPSS QoL indicates the view of the patient if always accompanied by current LUTS/BPH in a future life, among which are six options: from 0 (pleasurable) to 3 (acceptable), to 6 points (terrible), in turn. Therefore, although the score of QoL was only reduced by about one point, it meant a qualitative leap in the satisfaction of patients with the improvement of urination symptoms and reflected the need of the patient for treatment. Storage symptoms, especially the relief in nocturia, made a greater contribution to the improvement in QoL (32). These statistically significant results illustrated a great therapeutic effect of tadalafil in improving LUTS, but the specific mechanisms of action remain unclear. The PDE5 enzyme is expressed in the bladder, urethra, corpora cavernosa, prostate, ureter, and kidney (33). Matsukawa et al. (34) conducted a urodynamic-based study that demonstrated that tadalafil significantly improved bladder outlet obstruction and bladder storage function. In addition, in vitro studies showed that a PDE5I relaxed the smooth muscle of the bladder, neck, and prostate, and decreased detrusor muscle overactivity (35). The relaxant effect of PDE5Is on the bladder neck and urethra mediated by the NO-cGMP signaling pathway might result in symptom relief in patients with LUTS/BPH. Other related mechanisms include decreased activation of the RhoA/Rho kinase pathway, improvement of oxygenation, regulation of proliferation and transdifferentiation, modulation of the afferent nerves of the bladder and the prostate along with autonomic nervous system overactivity, and anti-inflammatory effects (7, 36). These mechanisms identified by our results might mediate the effective alleviation of the symptoms of BPH by this agent.

The corpus cavernosum, bladder, and prostate have similar pathophysiological pathways, and, therefore, LUTS/BPH and ED are often comorbid in the older population and have a higher incidence in older men (37). More importantly, LUTS is considered a risk factor for ED (38). Although many PDE5Is have similar mechanisms of action, tadalafil is the only PDE5I approved for the treatment of BPH because of its safety, tolerability, and longer duration of action (7). Nevertheless, a study of more than 1,000 men conducted by Broderick et al. (39) reported that tadalafil exhibited a similar efficacy in improving LUTS/BPH in men with or without comorbid ED. Moreover, Dong et al. (30) performed a subgroup analysis and reported that tadalafil showed a more significant improvement in BPH symptoms in men without ED than in those with ED. The effect of tadalafil on LUTS does not appear to mainly involve its mechanism of action on ED. However, the inhibitory effects of tamsulosin on neurogenic contractions have been reported to be enhanced by tadalafil in the human bladder, neck, and prostate. Those findings along with the study showing that cotreatment with ABs and tadalafil produces an additional relaxation effect on the corpus cavernosum in vitro (40, 41), suggests there might exist synergistic effects among tadalafil and tamsulosin accounting for the better effect in patients who are suffering from LUTS/BPH and ED. Thus, when an ABs or tadalafil alone does not show sufficient efficacy, cotherapy with both agents may be considered.

No statistically significant difference was found in Q_max and PVR in this study, which is consistent with the finding by Liu et al. (42). However, trials studying cotreatment with ABs and PDE5Is demonstrated that it increased the urinary flow rate (43, 44). The relaxant effect of PDE5Is on the bladder neck and prostate, which should have increased the urinary flow, might be counteracted by the concomitant relaxation of the detrusor muscle. Nevertheless, cotherapy may exert a synergistically positive effect on the detrusor muscle, thereby improving the urinary flow rate (12). More studies are required to elucidate the mechanism.

Although the difference in AEs was statistically significant, the side effects were mild and sustainable, such as headache, dyspepsia, and back pain. Furthermore, the difference in the incidence of SAEs was not significant. Interestingly, one patient reported an SAE in the tadalafil group whereas six participants reported in the placebo group of the study by Roehrborn (15) reported SAEs, suggesting that some AEs might be caused by psychological effects. Moreover, Wada et al. (45) demonstrated that the main reason for withdrawal of tadalafil was insufficient efficacy, followed by AEs and improvement of symptoms (45). In addition, calculated finally to be 2.5% on average, the incidence of discontinuation was low. Therefore, tadalafil 5 mg daily had no obvious adverse effects and is highly effective in improving LUTS/BPH.

Previous trials have reported that a higher baseline IPSS score correlates with a better therapeutic effect of ABs (46), which is consistent with our present observation (Figure 4A). Moreover, the improvement in IPSS appeared to be related to age and obesity (Figures 4B,C). These results suggested that younger, more obese men with more severe urinary symptoms may be the ideal candidates for tadalafil monotherapy. This could be explained by the changes in metabolism and hormonal levels that accompany aging and obesity. Testosterone levels decrease with increasing age and the hormonal dependency of PDE5 expression has been found in the animal models (47). Additional research is needed to further verify these results and explore the underlying mechanisms of action.

There are some limitations to our study that should be recognized. We were restricted to studies comparing tadalafil with placebo, rather than other pharmacological treatments recommended in guidelines to manage LUTS. Nonetheless, we focus on whether tadalafil is effective and safe in treating LUTS/BPH, rather than assessing which is better after comparing tadalafil and other drugs. In addition, relatively few experiments reported Q_max and PVR, and those that did were conducted before 2013, which may have caused the lack of statistical significance observed. More large-scale, well-designed, and long-term prospective clinical studies using comprehensive indicators should be conducted to further confirm the effectiveness and safety of tadalafil monotherapy in improving LUTS/BPH vs. active control.

Despite the several limitations to this study, we have reported the latest and most comprehensive evidence-based medical proof to demonstrate that 5 mg once daily tadalafil was effective and safe for the treatment of LUTS/BPH. All the studies in our analysis were RCTs and the follow-up deadline of 3 months was long enough, and the heterogeneity of our forest plots was also calculated to be low, except for the Q_max (I 2 = 52%). These findings indicate the reliability of the curative effect of tadalafil. As the population ages, more and more aging men are being troubled with LUTS/BPH together with ED. As an effective treatment for ED, tadalafil, shown in our study, has also a therapeutic effect in relieving LUTS/BPH. So, tadalafil is a better choice for men suffering from both LUTS/BPH and ED. What is more, due to its safety and tolerable AEs, tadalafil may provide another option for those who are intolerant to the side effects of ABs or 5ARIs. This study could provide a more meaningful reference for clinicians and researchers, and provide more concrete evidence for future guidelines for the treatment of BPH.

Conclusion

Treatment with 5 mg tadalafil once daily effectively improved total IPSS, IPSS voiding subscore, IPSS storage subscore, IPSS QoL, and BII. Moreover, monotherapy with tadalafil appeared to be well tolerated and safe because no significant difference was detected in SAEs between the tadalafil- and placebo-treated patients. Finally, 5 mg tadalafil administered once daily could be a therapeutic option for patients with LUTS/BPH.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Author Contributions

Conception and design, and administrative support by JW and QW. Provision of study materials or patients were administered by JC and DC. Collection and assembly of data were administered by JC, DC, YB, WW, and YX. Data analysis and interpretation were administered by JC, DC, and YB. Manuscript writing and final approval of manuscript were done by all the authors.

Funding

This work was funded by the National Natural Science Foundation of China (Grant no. 82000721 and no. 81770756); the Post-Doctor Research Project, West China Hospital, Sichuan University (Grant no. 2019HXBH089); and the Health Commission of Sichuan Province (Grant no. 20PJ036).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We would like to thank Editage (www.editage.cn) for the English language.

References

1. Madersbacher S, Sampson N, Culig, Z. Pathophysiology of benign prostatic hyperplasia and benign prostatic enlargement: A mini-review. Gerontology. (2019) 65:458–64. doi: 10.1159/000496289

2. Gratzke C, Bachmann A, Descazeaud A, Drake MJ, Madersbacher S, Mamoulakis C, et al. EAU guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. (2015) 67:1099–109. doi: 10.1016/j.eururo.2014.12.038

3. MacDonald R, Brasure M, Dahm P, Olson CM, Nelson VA, Fink HA, et al. Efficacy of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: A systematic review. Aging Male. (2019) 22:1–11. doi: 10.1080/13685538.2018.1434503

4. Lokeshwar SD, Harper BT, Webb E, Jordan A, Dykes TA, Neal DE Jr., et al. Epidemiology and treatment modalities for the management of benign prostatic hyperplasia. Transl Androl Urol. (2019) 8:529–39. doi: 10.21037/tau.2019.10.01

5. Morton A, Williams M, Perera M, Teloken PE, Donato P, Ranasinghe S, et al. Management of benign prostatic hyperplasia in the 21st century: Temporal trends in Australian population-based data. BJU Int. (2020) 126:18–26. doi: 10.1111/bju.15098

6. Yamanishi T, Kaga K, Sakata K, Yokoyama T, Kageyama S, Fuse M, et al. A randomized controlled study of the efficacy of tadalafil monotherapy versus combination of tadalafil and mirabegron for the treatment of persistent overactive bladder symptoms in men presenting with lower urinary tract symptoms (contact study). Neurourol Urodyn. (2020) 39:804–12. doi: 10.1002/nau.24285

7. Monica FZ, De Nucci. G. Tadalafil for the treatment of benign prostatic hyperplasia. Expert Opin Pharmacother. (2019) 20:929–37. doi: 10.1080/14656566.2019.1589452

8. Ückert S, Kedia GT, Tsikas D, Simon A, Bannowsky A, Kuczyk M.A. Emerging drugs to target lower urinary tract symptomatology (LUTS)/benign prostatic hyperplasia (BPH): Focus on the prostate. World J Urol. (2020) 38:1423–35. doi: 10.1007/s00345-019-02933-1

9. Sebastianelli A, Spatafora P, Morselli S, Vignozzi L, Serni S, McVary KT, et al. Tadalafil alone or in combination with tamsulosin for the management for LUTS/BPH and ED. Current Urology Reports. (2020) 21:56. doi: 10.1007/s11934-020-01009-7

10. Rezk MR, Tantawy MA, Wadie M, Weshahy S.A. Smart spectrophotometric assessment of tamsulosin hydrochloride and tadalafil in their new pharmaceutical formulation for treatment of benign prostatic hyperplasia and erectile dysfunction. Spectrochimica Acta. Part A. Molecular & Biomolecular Spectroscopy. (2020) 227:117547. doi: 10.1016/j.saa.2019.117547

11. Alhakamy NA, Fahmy UA, Ahmed O.A.A. Attenuation of benign prostatic hyperplasia by optimized tadalafil loaded pumpkin seed oil-based self nanoemulsion: In vitro and in vivo evaluation. Pharmaceutics. (2019) 11:640. doi: 10.3390/pharmaceutics11120640

12. Nagasubramanian S, John NT, Antonisamy B, Mukha RP, Jeyachandra Berry CS, Kumar S, et al. Tamsulosin and placebo vs tamsulosin and tadalafil in male lower urinary tract symptoms: A double-blinded, randomised controlled trial. BJU Int. (2020) 125:718–24. doi: 10.1111/bju.15027

13. Zhou Z, Zheng X, Wu J, Gao Z, Xu Z, Cui Y. Meta-analysis of efficacy and safety of tadalafil plus tamsulosin compared with tadalafil alone in treating men with benign prostatic hyperplasia and erectile dysfunction. Am J Mens Health. (2019) 13:1557988319882597. doi: 10.1177/1557988319882597

14. Zhang Z, Li H, Zhang X, Dai Y, Park HJ, Jiann BP, et al. Efficacy and safety of tadalafil 5 mg once-daily in Asian men with both lower urinary tract symptoms associated with benign prostatic hyperplasia and erectile dysfunction: A phase 3, randomized, double-blind, parallel, placebo- and tamsulosin-controlled study. Int J Urol. (2019) 26:192–200. doi: 10.1111/iju.13828

15. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: A dose finding study. J Urol. (2008) 180:1228–34. doi: 10.1016/j.juro.2008.06.079

16. Kim SC, Park JK, Kim SW, Lee SW, Ahn TY, Kim JJ, et al. Tadalafil administered once daily for treatment of lower urinary tract symptoms in Korean men with benign prostatic hyperplasia: Results from a placebo-controlled pilot study using tamsulosin as an active control. Low Urin Tract Symptoms. (2011) 3:86–93. doi: 10.1111/j.1757-5672.2011.00088.x

17. Porst H, Kim ED, Casabé AR, Mirone V, Secrest RJ, Xu L, et al. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: Results of an international randomized, double-blind, placebo-controlled trial. Eur Urol. (2011) 60:1105–13. doi: 10.1016/j.eururo.2011.08.005

18. Egerdie RB, Auerbach S, Roehrborn CG, Costa P, Garza MS, Esler AL, et al. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: Results of a randomized, placebo-controlled, double-blind study. J Sex Med. (2012) 9:271–81. doi: 10.1111/j.1743-6109.2011.02504.x

19. Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol. (2012) 61:917–25. doi: 10.1016/j.eururo.2012.01.013

20. Takeda M, Nishizawa O, Imaoka T, Morisaki Y, Viktrup L. Tadalafil for the treatment of lower urinary tract symptoms in Japanese men with benign prostatic hyperplasia: Results from a 12-week placebo-controlled dose-finding study with a 42-week open-label extension. Low Urin Tract Symptoms. (2012) 4:110–19. doi: 10.1111/j.1757-5672.2012.00144.x

21. Yokoyama O, Yoshida M, Kim SC, Wang CJ, Imaoka T, Morisaki Y, et al. Tadalafil once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A randomized placebo- and tamsulosin-controlled 12-week study in Asian men. Int J Urol. (2012) 20:193–201. doi: 10.1111/j.1442-2042.2012.03130.x

22. Brock G, Broderick G, Roehrborn CG, Xu L, Wong D, Viktrup L. Tadalafil once daily in the treatment of lower urinary tract symptoms(LUTS) suggestive of benign prostatic hyperplasia(BPH) in men without erectile dysfunction. BJU Int. (2013) 112:990–7. doi: 10.1111/bju.12251

23. Porst H, Roehrborn CG, Secrest RJ, Esler A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: Analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. (2013) 10:2044–52. doi: 10.1111/jsm.12212

24. Takeda M, Yokoyama O, Lee SW, Murakami M, Morisaki Y, Viktrup L. Tadalafil 5 mg once-daily therapy for men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: Results from a randomized, double-blind, placebo-controlled trial carried out in Japan and Korea. Int J Urol. (2014) 21:670–5. doi: 10.1111/iju.12410

25. Nishizawa O, Yoshida M, Takeda M, Yokoyama O, Morisaki Y, Murakami M, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: Analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. (2015) 22:378–84. doi: 10.1111/iju.12699

26. Oelke M, Wagg A, Takita Y, Büttner H, Viktrup L. Efficacy and safety of tadalafil 5 mg once daily in the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia in men aged ≥75 years: Integrated analyses of pooled data from multinational, randomized, placebo-controlled clinical studies. BJU Int. (2017) 119:793–803. doi: 10.1111/bju.13744

27. Yang DY, Jeong HC, Ko K, Lee SH, Lee SK, Shin TY, et al. Effect of tadalafil 5 mg on post-micturition dribble in men with lower urinary tract symptoms: A multicentre, double-blind, randomized, placebo-controlled trial. BJU Int. (2019) 124:862–69. doi: 10.1111/bju.14849

28. Calogero AE, Burgio G, Condorelli RA, Cannarella R, La Vignera S. Treatment of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction. Aging Male. (2018) 21:272–80. doi: 10.1080/13685538.2018.1432586

29. Singh I, Tk A, Gupta S. Efficacy and safety of tadalafil vs tamsulosin in lower urinary tract symptoms (luts) as a result of benign prostate hyperplasia (BPH)-open label randomised controlled study. Int J Clin Pract. (2020) 74:e13530. doi: 10.1111/ijcp.13530

30. Dong Y, Hao L, Shi Z, Wang G, Zhang Z, Han C. Efficacy and safety of tadalafil monotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia: A meta-analysis. Urol Int. (2013) 91:10–8. doi: 10.1159/000351405

31. Wang Y, Bao Y, Liu J, Duan L, Cui Y. Tadalafil 5 mg once daily improves lower urinary tract symptoms and erectile dysfunction: A systematic review and meta-analysis. Low Urin Tract Symptoms. (2016) 10:84–92. doi: 10.1111/luts.12144

32. Choi WS, Son H. The change of ipss 7 (nocturia) score has the maximum influence on the change of qol score in patients with lower urinary tract symptoms. World J Urol. (2019) 37:719–25. doi: 10.1007/s00345-018-2410-8

33. Rossanese M, Crestani A, Inferrera A, Giannarini G, Bartoletti R, Tubaro A, et al. Medical treatment for benign prostatic hyperplasia: Where do we stand? Urologia Journal. (2019) 86:115–21. doi: 10.1177/0391560319859785

34. Matsukawa Y, Majima T, Matsuo K, Funahashi Y, Kato M, Yamamoto T, et al. Effects of tadalafil on storage and voiding function in patients with male lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A urodynamic-based study. Int J Urol. (2018) 25:246–50. doi: 10.1111/iju.13489

35. Morelli A, Sarchielli E, Comeglio P, Filippi S, Mancina R, Gacci M, et al. Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats. J Sex Med. (2011) 8:2746–60. doi: 10.1111/j.1743-6109.2011.02416.x

36. Gacci M, Andersson KE, Chapple C, Maggi M, Mirone V, Oelke M, et al. Latest evidence on the use of phosphodiesterase type 5 inhibitors for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. (2016) 70:124–33. doi: 10.1016/j.eururo.2015.12.048

37. Kim SW, Park NC, Lee SW, Yang DY, Park JK, Moon DG, et al. Efficacy and safety of a fixed-dose combination therapy of tamsulosin and tadalafil for patients with lower urinary tract symptoms and erectile dysfunction: Results of a randomized, double-blinded, active-controlled trial. J Sex Med. (2017) 14:1018–27. doi: 10.1016/j.jsxm.2017.06.006

38. Kallidonis P, Adamou C, Kotsiris D, Ntasiotis P, Verze P, Athanasopoulos A. Combination therapy with alpha-blocker and phosphodiesterase-5 inhibitor for improving lower urinary tract symptoms and erectile dysfunction in comparison with monotherapy: A systematic review and meta-analysis. Eur Urol Focus. (2020) 6:537–58. doi: 10.1016/j.euf.2019.05.007

39. Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology. (2010) 75:1452–58. doi: 10.1016/j.urology.2009.09.093

40. Journal of Sexual Medicine. Conference: International Symposium on Prostate, A.a.M.s.S.H. J, Cuevas P, Fernandez A, La Fuente JM, Allona A, Moncada I, et al. Tadalafil enhances the inhibitory effects of tamsulosin on neurogenic contractions of human prostate and bladder neck. J Sex Med. (2012) 9:2293–306. doi: 10.1111/j.1743-6109.2012.02821.x

41. Oger S, Behr-Roussel D, Gorny D, Lebret T, Denoux Y, Alexandre L, et al. Combination of alfuzosin and tadalafil exerts an additive relaxant effect on human detrusor and prostatic tissues in vitro. Eur Urol. (2010) 57:699–707. doi: 10.1016/j.eururo.2009.04.039

42. Liu L, Zheng S, Han P, Wei Q. Phosphodiesterase-5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia: A systematic review and meta-analysis. Urology. (2011) 77:123–9. doi: 10.1016/j.urology.2010.07.508

43. Gacci M, Corona G, Salvi M, Vignozzi L, McVary KT, Kaplan SA, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with alpha-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. (2012) 61:994–1003.

44. Yan H, Zong H, Cui Y, Li N, Zhang Y. The efficacy of PDE5 inhibitors alone or in combination with alpha-blockers for the treatment of erectile dysfunction and lower urinary tract symptoms due to benign prostatic hyperplasia: A systematic review and meta-analysis. J Sex Med. (2014) 11:1539–45. doi: 10.1111/jsm.12499

45. Wada N, Kikuchi D, Tateoka J, Abe N, Watanabe M, Tamaki G, et al. Persistence rate with tadalafil for treatment of male lower urinary tract symptoms. Urol Int. (2020) 104:373–77. doi: 10.1159/000507230

46. Roehrborn CG, Siami P, Barkin J, Damiao R, Becher E, Minana B, et al. The influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the combat study. Eur Urol. (2009) 55:461–71. doi: 10.1016/j.eururo.2008.10.037

47. Morelli A, Filippi S, Sandner P, Fibbi B, Chavalmane AK, Silvestrini E, et al. Vardenafil modulates bladder contractility through cgmp-mediated inhibition of rhoa/rho kinase signaling pathway in spontaneously hypertensive rats. J Sex Med. (2009) 6:1594–608. doi: 10.1111/j.1743-6109.2009.01249.x

Keywords: benign prostatic hyperplasia (BPH), lower urinary tract symptoms (LUTS), tadalafil, efficacy, safety

Citation: Cui J, Cao D, Bai Y, Wang J, Yin S, Wei W, Xiao Y, Wang J and Wei Q (2021) Efficacy and Safety of 12-week Monotherapy With Once Daily 5 mg Tadalafil for Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia: Evidence-based Analysis. Front. Med. 8:744012. doi: 10.3389/fmed.2021.744012

Received: 19 July 2021; Accepted: 06 September 2021;
Published: 12 October 2021.

Xiulin Zhang, Second Hospital of Shandong University, China

Hui Ding, Lanzhou University Second Hospital, China
Zhangqun Ye, Huazhong University of Science and Technology, China

Copyright © 2021 Cui, Cao, Bai, Wang, Yin, Wei, Xiao, Wang and Wei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

† These authors have contributed equally to this work and share first authorship

This article is part of the Research Topic

Advances on Pathogenesis and Treatment of Lower Urinary Tract Symptoms and Pelvic Floor Dysfunction Diseases

The use of a single daily dose of tadalafil to treat signs and symptoms of benign prostatic hyperplasia and erectile dysfunction

This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

Abstract

A strong and independent association between lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED) has been widely evidenced in several clinical epidemiologic studies. Preclinical animal models have provided a great deal of information on potential common pathogenic mechanisms underlying these two clinical identities. Although the efficacy of the most commonly used treatments for LUTS/BPH is well defined, the negative impact of these treatments on sexual function – in particular, on ED – has triggered the search for new treatment options. In this regard, a new role for phosphodiesterase type 5 inhibitors in the treatment of LUTS/BPH and ED has been claimed. Tadalafil is one of the most extensively investigated phosphodiesterase type 5 inhibitors for this new indication. All evidence reported to date suggests that tadalafil 5 mg once daily is a safe and effective treatment option for both LUTS/BPH and ED.

Introduction

During the last decade, several preclinical and clinical studies have been initiated to investigate the links between lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED).1 The reported evidence is based on single and multicenter trials from general and/or uro-/andrological populations; however, trial outcomes have been controversial.

Although the efficacy of all currently available treatments for LUTS/BPH is well defined, the negative impact of all therapies on erectile function (EF) is still under evaluation. Lifestyle modifications and phytotherapies have no or minimal impact on sexual function but these are also less effective on lower urinary tract symptoms (LUTS). In contrast, α-blockers, 5α-reductase inhibitors, and prostatic surgery, although associated with a strong improvement in LUTS, are usually associated with worsening sexual function.1

Several clinical trials have extensively reported on the efficacy and safety of chronic treatment with phosphodiesterase type 5 inhibitors (PDE5-Is) – either alone or in combination with conventional therapies – in ameliorating LUTS in men with or without ED.2

The aims of the present review were to analyze the links between LUTS/BPH and ED, examine the efficacy and safety of current treatment options for LUTS/BPH, and summarize the literature concerning the use of tadalafil for the treatment of LUTS/BPH, including randomized controlled trials (RCTs) and systematic and nonsystematic reviews of this topic.

The emerging links between LUTS and ED in aging men

Epidemiologic data

Many authors have analyzed the association between LUTS/BPH and ED in aging men.3 The strong and independent relationship between LUTS and ED has been shown in several epidemiologic trials. The positive association of LUTS severity with clinically relevant ED – independent of well-known causes of ED such as age, diabetes, medications, or coronary artery disease – has strongly suggested a common pathogenetic mechanism.

The National Health and Social Life Survey suggested that LUTS are a significant risk factor for ED, with an odds ratio (OR) of 3.13 in 1410 men aged 18–59 years.4 In the Krimpen study, which included men aged 50–78 years, the prevalence of severe ED was tenfold higher in men aged 70–78 years than in those aged 50–54 years. Logistic regression showed that, regardless of age, severe LUTS were strongly associated with ED (OR 7.5; compared with no LUTS).5 The Asian Survey of Aging Males, a study on 1155 men aged 50–80 years, demonstrated that males with severe LUTS were three times more likely to have ED than those without LUTS (OR 3.17).6 In recent times, the Boston Area Community Health Survey investigated 5506 men aged 30–80 years and suggested that the relationship between LUTS and ED is primarily due to symptoms of prostatitis, incontinence, and nocturia (OR for ED: 1.86, 1.73, and 0.76 for prostatitis, incontinence, and nocturia respectively).7 In this study, only age > 60 years, diabetes, and low socioeconomic status were more relevant than LUTS as predictive factors for ED.

In a study of 1420 men with LUTS, although age has been shown to be the most important predictor of sexual function, benign prostatic hyperplasia (BPH)-related symptoms (according to the Benign Prostatic Hyperplasia Impact Index [BII]), as well as general quality of life (QOL) were also predictive for sexual dysfunction, including ED. In contrast, uroflowmetry parameters or post-void residual (PVR) urine volume were not associated with sexual dysfunction.8 In a representative population sample of 4489 German men aged 30–80 years (Cologne Male Survey11), the overall prevalence of ED was 19.2%, ranging from 2% in men in their 40’s to 53% in men in their 80s; the prevalence of LUTS was 72.2% in men with ED, compared with 37.7% in those without ED. The Multinational Survey of the Aging Male (MSAM-7) investigated 12,815 men aged 50–80 years and demonstrated an ED prevalence of 43.0%, 65.8%, and 82.5% in men with mild, moderate, and severe LUTS, respectively; severe LUTS resulted in an OR of 7.67 for ED.9 The Epidemiology of LUTS survey of 11,834 men with a mean age of 56 years showed that men with LUTS had more severe ED; additionally, urgency with fear of urinary leakage and leakage during sexual activity were also positively associated with ED.10

In a recent comprehensive review that summarized data obtained in 20 community- and clinical-based studies of 71,322 men, a positive correlation between LUTS and ED was demonstrated, with the overall ORs ranging from 1.4 to 9.74.11

Taken together, this evidence implies that both LUTS/BPH and ED are associated with aging, but that the association between severity of LUTS/BPH and ED is independent of age. Alterations in mechanisms associated with metabolic syndrome and cardiovascular disorders are crucial to understanding the pathways and underlying links between these symptoms.

Common pathways linking LUTS/BPH and ED

The pathophysiology of LUTS/BPH and ED is complex and likely to be multifactorial involving numerous mechanisms affecting the entire lower urinary tract (LUT). The major mechanisms determining LUTS have been extensively reviewed elsewhere.12 Briefly, these are: reduced nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) mainly in the prostate, urethra, and bladder but also in the pelvic neuronal and vascular bed; increased RhoA kinase pathway activity; increased autonomic nerve activity; and pelvic hypoxygenation and ischemia.

The altered balance between relaxation (reduced NO/cGMP-signaling) and contraction (increased RhoA/Rho kinase activity) in the penile smooth muscle compartment, as well as penile hypoxygenation/ischemia, are pathogenic factors underlying ED. Essentially, in animal models of ED associated with cardiovascular diseases – including hypertension, diabetes, and metabolic syndrome or neurogenic ED15–17 – the concomitant impairment of smooth muscle relaxation and reduced oxygenation were documented.

In humans, phosphodiesterase type 5 (PDE5) is expressed in the whole of the LUT, including the urethra, prostate, and bladder – all potential targets of PDE5-Is.13–16 In all these organs, PDE5 was prominently localized in the stroma and in the vascular bed (endothelial and smooth muscle cells), suggesting a possible action of PDE5-I either on smooth muscle contraction and/or blood flow. Animal models have provided a great deal of information on the possible mechanisms of action of PDE5-Is, including the effects of tadalafil on LUT. Chronic pelvic ischemia was one of the main determinants of the functional and morphological changes observed in both bladder and prostate in the spontaneous hypertensive rat model.16,23

Chronic treatment with tadalafil or other PDE5-I in the spontaneous hypertensive rat was able to counteract all these LUT alterations, most likely through an increased blood perfusion and LUT oxygenation.15,16 A similar effect of tadalafil concerning increasing tissue perfusion and oxygenation has also been described in an animal model of severe neurogenic ED; chronic treatment with tadalafil after bilateral cavernous nerve neurotomy in the rat normalized penile oxygenation as well as smooth muscle content. One of the best described mechanisms of action of PDE5-Is with regard to inducing vasodilatation and increasing blood flow is smooth muscle cell relaxation of the LUT mediated by NO/cGMP.15,16 In addition, modulation of autonomic nervous system overactivity and bladder/prostate afferent nerve activity by PDE5-Is has also been suggested.12,19,20

Recently, it was documented that tadalafil enhances prostate and bladder neck relaxation through the inhibition of neurogenic contractions.18 Accordingly, it has been demonstrated that PDE5-Is induce a cGMP/protein kinase G-mediated inhibition of the contractile RhoA/Rho-associated protein kinase signaling in the bladder,19 which also suggests a crucial role of PDE5-Is in ameliorating the dynamic/functional component of LUTS/BPH pathogenesis. These preclinical hypotheses have been confirmed by clinical evidence with PDE5-Is in spinal cord injured men investigated by urodynamics20 and in men under sexual rehabilitation for post-prostatectomy ED.21

A specific action of tadalafil in counteracting the pathogenic factors mainly related to the static component of LUTS (ie, prostate enlargement and urethral compression) has been demonstrated as well.18 We recently reported, for the first time, a specific action of tadalafil on the prostatic chronic inflammatory process, the third recognized pathogenetic component of LUTS/BPH.22,23,28

Although primarily characterized by increased proliferation of both fibroblastic stromal and epithelial cells, intraprostatic chronic inflammation has also been documented to play a causative role in LUTS/BPH. From a pathophysiological standpoint, an autocrine/paracrine proinflammatory loop between chronically activated T cells and stromal cells seems to be the key determinant factor in BPH development and progression.24

The prostate of the adult male rabbit fed a high fat diet (HFD) developed severe histological inflammation coupled with stromal derangement and hypoxia.25–30 HFD-induced Metabolic Sydrome (MetS)-like features were associated with marked histological alterations of the prostate gland, characterized by severe inflammation coupled with stromal derangement and hypoxia. Interestingly, the HFD prostate showed also a marked increased expression of PDE5, suggesting that prostate in MetS condition could be the optimal target for PDE5-Is. PDE5 expression in the prostate was also strongly and positively associated with the expression of several inflammatory, myofibroblast activation, and hypoxia-related markers.28

Chronic use of a PDE5-I (12-week treatment with tadalafil) reduced the expression of inflammatory, pro-fibrotic, and myofibroblast activation markers in the prostate.28 Consistent with these data, it has previously been reported that tadalafil strongly attenuated tumor growth factor beta 1-induced fibroblast-to-myofibroblast trans-differentiation in primary human prostate stromal cells.31 Short-term treatment (1 week) with tadalafil was also able to significantly blunt HFD-related prostatic alterations, mainly reducing the inflammatory process. A significant reduction in interleukin 8, tumor necrosis factor alpha, and genes related to tissue remodeling was observed.28 Interleukin 8 is considered as a reliable surrogate marker of prostatic inflammatory diseases,32 linking chronic inflammation to prostatic enlargement. In particular, an increase in subtype-1 T-helper cells (Th1) is crucial in loss of self-tolerance and autoimmune-tissue remodeling with hyperplastic overgrowth. Interestingly, we found that Th1 was absent from healthy rabbit prostate but was significantly induced by an HFD.23,27

Remarkably, both acute and chronic treatment with tadalafil dramatically reduced Th1 immune response in the prostates of animal subject on HFDs, further indicating the inhibitory action of PDE5-Is on the inflammatory processes affecting the prostate during metabolic derangements. Therefore, animal models demonstrated that both chronic and acute tadalafil administration were effective in reducing the HFD-related prostatic alterations, mainly attenuating chronic inflammatory and pro-fibrotic processes.28 Other positive effects of tadalafil on LUT oxygenation have also been reported.16

In conclusion, these experimental findings in animals and studies in humans add new insights into the understanding of the mechanism of action of PDE5-Is, and in particular of tadalafil, in alleviating LUTS (even in MetS patients). Study results strongly support the multiple potentiality of this drug class.

Active treatments for LUTS/BPH and their impact on sexual function

Active treatments include phytotherapy, conventional medical therapies, and surgical procedures (minimally invasive or invasive).33 The more invasive the treatment, the greater the occurrence of adverse events (AEs). Consequently, while invasive surgery (eg, transurethral resection of the prostate [TURP]) can sufficiently and quickly decrease symptoms or signs of BPH, it is also associated with well-defined severe AEs, such as bleeding, the need for blood transfusions, transurethral resection syndrome, urinary incontinence, and ED. Therefore, it is crucial that any treatment for LUTS/BPH relieves the LUTS without producing major or troublesome AEs. Both medical and surgical treatments can have problematic side effects, including a remarkable worsening of sexual function, but these particular AEs appear in different treatment modalities with different probabilities.1

The efficacy of the various treatments and any sexual dysfunction/ED side effects they might produce have been well documented for the various treatment options of LUTS/BPH.

Phytotherapy

The evidence of phytotherapy for LUTS/BPH has strikingly increased during the last two decades. Plant extracts contain a large variety of chemical components, including phytosterols, plant oils, fatty acids, and phytoestrogens, which have various biochemical effects – including anti-inflammatory, antioxidant, and inhibitory – on 5α-reductase. In the TransEuropean Research Into the Use of Management Policies for LUTS suggestive of BPH in Primary Healthcare (TRIUMPH) study, Serenoa repens and Pygeum africanum, the most used phytotherapeutic agents, both produced an equally significant improvement in LUTS in 43% of patients, giving a mean change of 3 International Prostate Symptom Score (IPSS) points but were less effective than α-blockers or 5α-reductase inhibitors (5ARIs).34 However, only mild and infrequent AEs, with particular concern regarding the impact on sexual function, (decreased libido) or gastrointestinal function, have been reported. In a trial with 811 LUTS/BPH patients, the incidence of ejaculatory dysfunction was reported to be significantly lower with Serenoa repens than with tamsulosin (0.6% vs 4.2% respectively).35 In another study on 2511 men, an increase in sexual dysfunction, evaluated using the Male Sexual Function-4 questionnaire, was reported with tamsulosin (+0.3) and finasteride (+0.8), while a slight improvement with Serenoa repens (−0.2) was documented.36

Medical therapies

Medical therapies for LUTS/BPH mainly include α-blockers and 5ARIs, alone or in combination, with well-established efficacy and AE profiles.1 In the TRIUMPH study, which recorded the treatment and outcomes of 2351 newly presenting LUTS/BPH patients in six European countries over 3 years, the use of α-blockers alone resulted in the most effective monotherapy, with a mean reduction of 6.3 IPSS points. In contrast, 5ARIs reduced LUTS by only 4.1 IPSS points. However, a statistically significant advantage resulted when using the combination therapy of tamsulosin plus finasteride, which resulted in a decrease of 8.1 IPSS points.34

Despite the fact that some α-blockers (eg, alfuzosin) improved EF in some trials, ejaculatory dysfunction was usually reported in these trials, occurring in 2%–14% of patients.37 Further, several sexual AEs have been reported to result from treatment with 5ARIs, including impaired sexual desire or loss of libido in 2%–10% of patients, ED in 3%–16%, and ejaculatory dysfunction in 0%–8%.38 The Combination of Avodart and Tamsulosin (CombAT) study evaluated tamsulosin and dutasteride combination therapy in 4844 men with signs and symptoms of BPH; after 24 months, the rate of ED was 3.8% with tamsulosin, 6.0% with dutasteride, and 7.4% with combination therapy.39

Minimally invasive procedures

In recent years, a number of minimally invasive therapies for LUTS/BPH have been developed and refined, including transurethral needle ablation (TUNA), transurethral microwave thermotherapy, and interstitial laser coagulation. Although these procedures are less effective at relieving LUTS/BPH than conventional surgical treatments (eg, TURP) – with a mean 10.2 and 9.1 IPSS point reduction at 1 year for transurethral microwave thermotherapy and TUNA, respectively40 – AEs such as bleeding, ED, or ejaculatory dysfunction occur at a lower frequency. Consequently, their attractiveness for both patients and physicians is increasing. In a systematic review and meta-analysis of TUNA in symptomatic BPH patients, ED was reported in only 0.3% of men, retrograde ejaculation in 0.2%, and loss of ejaculation in 0.08% 41

Conventional and new surgical treatments

If treatment with drugs proves insufficient, the surgical gold standard for moderate to severe LUTS/BPH in patients with prostate volumes of less than 80–100 mL is TURP, which has replaced open prostatectomy (OP).42 Alternatively, for men with a prostate volume of ≤30 mL, transurethral incision of the prostate or bladder neck incision may be undertaken. A retrospective meta-analysis of 3304 men treated by conventional surgical therapies reported retrograde ejaculation in 6%–80% of patients after OP, 70% after TURP, and 39% after transurethral incision of the prostate. ED was reported in 13% of patients after TURP and in 11% after OP.43 The newest treatments for signs or symptoms of BPH are holmium laser enucleation of the prostate and photoselective vaporization of the prostate; fewer AEs (eg, bleeding or blood transfusions) have been reported for both procedures than for conventional surgery, but their impact on sexual function was almost the same.44

Although the efficacy and AE profiles of all currently available treatment options for LUTS/BPH have been well investigated and defined, outcomes are sometimes unsatisfactory for patients and partners, mainly due to the postoperative AEs – above all, those affecting sexual function. These treatment-related disadvantages have triggered the search for new treatment options for effective relief of LUTS that result in very few or no sexual or other AEs. PDE5-I treatment (eg, with tadalafil [Cialis™, Eli-Lilly, Indianapolis, IN, USA]) seems to combine the efficacy of drugs (α-blockers) and can maintain or even improve sexual function.

Clinical evidence for tadalafil for LUTS/BPH

In 2007, McVary et al45 evaluated for the first time the efficacy and safety of tadalafil for the treatment of LUTS/BPH in men with or without ED. A total of 479 patients were screened and, after a 4-week washout and 4-week placebo run-in period, 281 were randomly assigned to a 6-week treatment with once-daily placebo or tadalafil 5 mg. After 6 weeks, the remaining 261 patients were assigned to continue with placebo for another 6 weeks (a total of 12 weeks of once-daily placebo treatment) or to dose escalate tadalafil to 20 mg once daily. Of 143 placebo-assigned patients, 121 (84.6%) were sexually active, 84 (59.2%) had no ED, and 76 (53.1%) were sexually active despite ED, while, of 138 men treated with 5 or 20 mg tadalafil, 107 (77.5%) were sexually active, 99 (71.7%) had normal sexual function, and 80 (58.0%) were sexually active despite ED. Patients were evaluated for LUTS using the IPSS (including the IPSS-QOL question) and BII questionnaires. Maximum urinary flow rate (Q_max) and average urinary flow rate (Q_ave) of free uroflowmetry were recorded, post-void residual urine (PVR) was measured by ultrasound after uroflowmetry, and sexual function was studied by using the erectile function (EF) domain of the International Index of Erectile Function (IIEF) questionnaire (questions 1 to 5 and 15).

In McVary et al’s study,45 tadalafil significantly improved LUTS at week 6 (mean IPSS change from baseline for 5 mg tadalafil was −2.8 compared with −1.2 for placebo) but improvement of LUTS was even better at week 12 with dose escalated tadalafil (5/20 mg tadalafil −3.8 vs placebo −1.7). BII changes observed were −0.7 for tadalafil 5 mg versus −0.4 for placebo at week 6 and −1.3 for tadalafil versus −0.6 for placebo at week 12. No significant changes of uroflowmetry parameters were observed after week 12 between placebo and tadalafil: Q_max 2.3 mL/s versus 2.7 mL/s (P = 0.81); Q_ave 1.1 mL/s versus 0.9 mL/s (P = 0.79). Additionally, there was no change of PVR between the groups: −1.2 mL versus −2.5 mL (P = 0.57). As expected, sexual activity, as measured by the IIEF questionnaire, significantly improved only with tadalafil (+8.4) compared with placebo (+1.6; P < 0.001) after week 12. Also in this study, the authors were the first to evaluate the safety profile for PDE5-Is in patients with LUTS/BPH. The most commonly reported AEs (>2%) were dyspepsia, back pain, headache, nasopharyngitis, and upper respiratory tract infection (each AE occurred in ≤5.1%). As expected, erections improved after 12 weeks with 5/20 mg tadalafil in 5.1%. Thus, in this study, McVary et al demonstrated for the first time that tadalafil is an effective and safe treatment for LUTS/BPH; patients achieved an effective LUTS response without significant AEs but with improvement of concomitant ED.

In 2008, Roehrborn et al46 published their report on a randomized, double-blind, placebo-controlled, 12-week study performed in ten countries and 92 centers in order to evaluate the optimal dose of tadalafil for the treatment of LUTS/BPH. The authors included 1813 LUTS/BPH patients aged 45 years or older. After a 4-week washout and 4-week placebo run-in period, the study population was equally divided into five treatment arms: either (1) placebo or tadalafil (2) 2.5 mg, (3) 5 mg, (4) 10 mg, or (5) 20 mg once daily. Patients were assessed at baseline and at weeks 4, 8, and 12. At week 12, patients’ IPSS had significantly improved for all tadalafil doses compared with placebo. However, the best IPSS/QOL/AE ratios were obtained with tadalafil 5 mg. Compared with placebo (decrease of 2.3 IPSS points), improvement of IPSS was 3.9 for tadalafil 2.5 mg (P < 0.015), 4.9 for tadalafil 5 mg (P < 0.001), 5.2 for tadalafil 10 mg (P < 0.001), and 5.2 for tadalafil 20 mg (P < 0.001). In terms of safety profile, back pain, myalgia, and headache were more frequent at higher tadalafil doses. AEs reported in the placebo arm versus 2.5/5/10/20 mg tadalafil arms were: six (2.8%) versus five, six (2.8%), eleven (5.1%), and seven (3.3%) for headache; zero versus two (1.0%), ten (4.7), six (2.8%), and ten (4.8%) for dyspepsia; and one (0.5%) versus three (1.4%), two (0.9%), ten (4.6%), and twelve (5.7%) for back pain. AEs led to study discontinuation for 2.4% of placebo-treated men versus 1.9%, 5.7%, 5.1%, and 6.7%, respectively, of 2.5/5/10/20 mg tadalafil-treated males. Thus, this study determined that tadalafil 5 mg once daily is the best dosage for the treatment of LUTS/BPH, providing an effective response to LUTS, with a minimal occurrence of AEs and rate of discontinuation.

Also in 2008, Bechara et al47 considered combination therapy of tadalafil with an α-blocker for the treatment of LUTS/BPH for the first time and compared tamsulosin 0.4 mg with tamsulosin 0.4 mg plus tadalafil 20 mg once daily. They enrolled 30 men with LUTS/BPH of at least 6 months in a randomized, double-blind, crossover study. Patients were treated with monotherapy or combination therapy for 45 days and then switched to the other treatment mode for another 45 days. The authors found a significant improvement in IPSS (tamsulosin −6.7 vs tadalafil/tamsulosin −9.2; P < 0.05) and for the QOL question in the IPSS questionnaire (IPSS-QOL) (P < 0.001) with both treatment modalities compared with baseline but differences were greater with combination therapy. In terms of Q_max and PVR, there was a significant improvement from baseline with both treatment regimens (P < 0.001) but no significant differences between tamsulosin alone versus tamsulosin plus tadalafil 20 mg (P > 0.05). Improvement in IIEF score was significant with tamsulosin plus tadalafil (P < 0.001) but not with tamsulosin alone (P > 0.05). In this study, therefore, the authors demonstrated for the very first time that combination therapy is more efficacious when adding a PDE5-I (tadalafil) to standard treatment (tamsulosin) than α-blocker monotherapy.

In 2009, Liguori et al48 considered the combination of tadalafil 20 mg with alfuzosin 10 mg for the treatment of LUTS/BPH and ED. The authors enrolled 66 men who were randomized to either alfuzosin 10 mg once daily (22 patients), tadalafil 20 mg on alternate days (21 patients), or a combination of both (23 patients) and assessed treatment outcomes at baseline and at week 12. They did not find a significant IPSS improvement for tadalafil alone (−8.4%, P not significant) but demonstrated a significant reduction in IPSS for alfuzosin monotherapy (−27.2%, P < 0.003) and combination therapy (−41.6%, P < 0.001). As such, Liguori et al confirmed the improved efficacy of improving LUTS/BPH (according to IPSS) with combination therapy (α-blockers plus a PDE5-I) compared with monotherapy (α-blocker or PDE5-I). Furthermore, the authors found an increased efficacy for EF and uroflowmetry parameters when using the combination therapy: IIEF +37.6% (P < 0.001) and Q_max +29.6% (P < 0.001) versus α-blocker monotherapy (IIEF +15.0%, P = 0.026; Q_max +21.7%, P = 0.006) or tadalafil monotherapy (IIEF +36.3%, P = 0.011; Q_max +9.5%, P = 0.044). At the end of the trial, 15 AEs (55.5%) occurred in the combination therapy arm and five (18.5%) in the tamsulosin/placebo arm; headache was the most reported AE: two patients discontinued the study due to AEs. This trial confirmed the efficacy and safety of combination therapy, even when using another α-blocker (alfuzosin) compared with α-blocker monotherapy.

In 2009, Porst et al49 investigated a selected group of 581 men with comorbid LUTS/BPH and ED who reported being sexually active. Mean age was 62 years and mean body mass index (BMI) was 28.3 kg/m 2 . The majority of patients (84.5%) had had LUTS/BPH for more than 1 year, and 50.4% had a LUTS/BPH history > 3 years. After 4-week washout period for patients taking BPH and/or ED drugs and 4-week placebo run-in period, patients were assigned to once-daily placebo or tadalafil 2.5, 5, 10, or 20 mg for 12 weeks. At baseline, the majority of patients had moderate ED (IIEF score of between 11 and 16): 60.0% in the placebo group, 57.5% in the tadalafil 2.5 mg group, 57.3% in the tadalafil 5 mg group, 48.3% in the tadalafil 10 mg group, and 57.8% in the tadalafil 20 mg group. Improvement in IPSS from baseline to study end was significantly greater for all tadalafil doses versus placebo: −2.1 for placebo, −3.6 for tadalafil 2.5 mg (P = 0.043), −4.2 for tadalafil 5 mg (P = 0.004), −4.7 for tadalafil 10 mg (P < 0.001), and −4.7 for tadalafil 20 mg (P = < 0.001). Q_max was not significantly different for any tadalafil group versus placebo. In terms of sexual function in men with an IIEF score < 26 at baseline, normal EF (IIEF ≥ 26) was dose-dependently obtained for tadalafil-treated men: 21.2% with tadalafil 2.5 mg, 34.2% with tadalafil 5 mg, 42.5% with tadalafil 10 mg, and 40% for tadalafil 20 mg versus 14% for placebo-treated men. AEs occurring in ≥2% of tadalafil-treated patients were headache, dyspepsia, back pain, and myalgia. For the 2.5, 5, 10, and 20 mg tadalafil groups, the discontinuation frequency due to AEs was 2.7%, 5.1%, 5%, and 5.2%, respectively. Thus, this dose-finding study confirmed the efficacy of tadalafil 5 mg once daily in ameliorating LUTS/BPH and corroborated the role of this daily treatment in the concomitant improvement of EF in LUTS/BPH men with or without ED.

Also in 2009, for the first time, Roehrborn et al50 specifically evaluated uroflowmetry data in LUTS/BPH patients treated with tadalafil once daily. After a 4-week placebo run-in period, they enrolled 1058 LUTS/BPH patients and randomly allocated these men to receive once-daily treatment with placebo or tadalafil (2.5, 5, 10, or 20 mg) for 12 weeks. Uroflowmetry variables were stratified by age, Q_max, LUTS severity, prostate size, previous α-blocker use, and sexual activity, including ED history. The authors demonstrated that tadalafil was able to induce a dose-dependent increase in Q_max, although not one that was significantly different from placebo (1.4 mL/s [+15%] for tadalafil 2.5 mg, 2.0 mL/s [+22%] for tadalafil 20 mg, and 1.2 mL/s [+12%] for placebo). Moreover, age, Q_max severity at baseline, ED history, sexual activity, and previous treatment with α-blockers were determinants for the change in Q_max across all tadalafil and placebo treatment groups. In tadalafil 2.5, 5, 10, or 20 mg once daily groups, there were study discontinuations due to AEs in 1.9%, 5.7%, 5,1% and 6.7%, respectively. Once again, the lack of a significant Q_max improvement was documented in this trial; this finding has since been confirmed by sub-analyses of other tadalafil trials.2

In 2010, Dmochowski et al51 conducted a multicenter, randomized, double-blind, placebo-controlled, 12-week trial comparing once-daily tadalafil 20 mg with placebo in LUTS/BPH men with or without bladder outlet obstruction. Invasive computer-urodynamic evaluation, free uroflowmetry, and IPSS were assessed in this study. However, men with severe bladder outlet obstruction were not included in this study. In 101 placebo-treated patients (mean age 59 years and BMI 29.4 kg/m 2 ), mean Q_max was 13.3 ± 7.4 mL/s and mean PVR 59.3 ± 60.9 mL, while the 99 tadalafil-treated patients (mean age 58.2 years and BMI 29.5 kg/m 2 ) had a mean Q_max of 15.4 ± 11.1 mL/s and a mean PVR of 45.7 ± 49.6 mL. The differences of Q_max and Q_ave between men treated with tadalafil 20 mg versus placebo were not statistically significant for free uroflowmetry (mean difference of change from baseline tadalafil vs placebo: Q_max −0.6 mL/s and Q_ave +1 mL/s) or pressure flow study (Q_max −0.1 mL/s and Q_ave +0.1 mL/s). The incidence of AEs was higher in the tadalafil group (55.6%) than in the placebo group (27.7%), but discontinuations due to AEs were low in both groups (tadalafil 2.0% vs placebo 1.0%). In this safety study using a high dosage of tadalafil (20 mg for 12 weeks), Dmochowski et al suggested that once-daily administration of tadalafil should not worsen urodynamic parameters in men with LUTS/BPH.

In 2011, Porst et al52 evaluated the efficacy and safety of once-daily tadalafil 5 mg for the treatment of LUTS/BPH in an international, randomized, double-blind, placebo-controlled, 12-week trial. The authors screened 442 men and, after 4-week washout period and 4-week placebo run-in period, randomized 325 patients to receive placebo or tadalafil 5 mg once daily. From baseline to endpoint, tadalafil significantly improved IPSS in comparison to placebo (−5.6 vs −3.6, P = 0.004). There was a significant reduction in IPSS already at week 4 (tadalafil 5 mg −5.3 vs placebo −3.5, P = 0.003) and after week 12. Likewise, the BII score had already sig nificantly improved at week 4 (tadalafil 5 mg −1.8 vs placebo −1.2, P = 0.029) and continued to improve until week 12 (tadalafil 5 mg −1.8 vs placebo −1.3, P = 0.057). As in other studies, Porst et al found a remarkable improvement in IIEF in sexually active men with ED who were treated with tadalafil 5 mg versus placebo (+6.7 vs +2.0, P < 0.001) at week 12. The incidence rate of at least one AE was 22% and 26.1%, and one (0.6%) and six (3.7%) patients discontinued due to AEs in the placebo and tadalafil 5 mg groups, respectively. As such, this study demonstrated that the clinical efficacy of tadalafil 5 mg once daily in treatment of LUTS/BPH is already detectable after 4 weeks.

In 2011, Donatucci et al53 evaluated the long-term efficacy and safety of tadalafil for LUTS/BPH. They enrolled 427 men who had been investigated in a 12-week, placebo-controlled, dose-finding study with once-daily tadalafil (2.5, 5, 10, or 20 mg) or placebo46 and continued treatment in the open-label extension study with tadalafil 5 mg for 52 weeks. Independent of the dosage used in the 12-week dose-finding period, at endpoint, there was an improvement of −5.0 ± 6.7 points in IPSS and of 5.9 ± 7.6 points in IIEF score. After 1 year, compared with at week 12, a further improvement in total IPSS and storage and voiding sub-scores was reported (−0.9 ± 5.7, −0.3 ± 2.6, and −0.6 ± 3.6, respectively). The most common AEs (≥2%) were dyspepsia, gastroesophageal reflux disease, back pain, headache, sinusitis, hypertension, and cough. A total of 22 men (5.2%) discontinued the study due to AEs. Thus, this long-term study showed that tadalafil 5 mg once daily is well tolerated during a treatment period of 1 year and that the drug maintains or even improves storage and voiding symptoms, but the cost-effectiveness of the long-term chronic use of tadalafil was not evaluated.

In 2012, Oelke et al54 evaluated for the first time tadalafil 5 mg and tamsulosin 0.4 mg once daily for the treatment of LUTS/BPH in an international, placebo-controlled, randomized, double-blind, 12-week trial comparing separately and independently these two drugs with placebo. Following screening and washout, if needed, and a 4-week placebo run-in, they evaluated 511 men who were randomly assigned to placebo (n = 172), tadalafil 5 mg (n = 171), or tamsulosin 0.4 mg (n = 168). Compared with placebo, there was a significant decrease in IPSS of 1.5 points after only 1 week of treatment with tadalafil or tamsulosin (P < 0.01). After 12 weeks, decrease in IPSS with tadalafil (2.1 points, P = 0.001) was even more pronounced than with tamsulosin (1.5, P = 0.023) compared with placebo. Additionally, BII score had significantly improved at week 4 with tadalafil (−0.8; P < 0.001) and tamsulosin (−0.9; P < 0.001) and at week 12 (tadalafil −0.8, P = 0.003; tamsulosin −0.6, P = 0.026) compared with placebo. QOL (IPSS-QOL), treatment satisfaction (Treatment Satisfaction Scale), and Patient or Physician Global Impression of Improvement scores only improved for tadalafil, not for placebo or tamsulosin. Improvement in IIEF score was once more documented for tadalafil (4.0, P < 0.001) but not for tamsulosin (−0.4, P = 0.699) compared with placebo. The patient discontinuation rate due to AEs was 1.2% for placebo, 1.2% for tadalafil 5 mg, and 0.6% for tamsulosin 0.4 mg. The unexpected outcome of this study was the significant improvement of uroflowmetry parameters. Q_max and Q_ave similarly increased with both tadalafil (2.4 mL/s, P = 0.009 and 1.6 mL/s, P = 0.002, respectively) and tamsulosin (2.2 mL/s, P = 0.014 and 1.3 mL/s, P = 0.023, respectively) at week 12. In this trial, therefore, Oelke et al54 demonstrated a significant and clinically meaningful improvement in LUTS/BPH with tadalafil 5 mg once daily, which was similar to that attained by tamsulosin 0.4 mg once daily after only 1 week, a further improvement in LUTS/BPH after 12 weeks, improvement of QOL and treatment satisfaction parameters only with tadalafil, and an unexpected but remarkable improvement of urinary flow rates at week 12.

Also in 2012, Regadas et al55 evaluated for the first time the effects on free uroflowmetry of treating patients with LUTS/BPH for 30 days with tamsulosin 0.4 mg with or without tadalafil 5 mg in a cohort of 40 men with bladder outlet obstruction (mean ± standard deviation: Q_max 6.2 mL/s ± 2.6 for α-blockers alone and 7.4 mL/s ± 2.6 for an α-blocker plus tadalafil). Patients were equally randomized into two treatment arms: once-daily tamsulosin 0.4 mg plus tadalafil 5 mg or tamsulosin 0.4 mg plus placebo. The study design included an urodynamic study based on the recommendations of the International Continence Society. Detrusor pressure at maximum flow was significantly reduced with tamsulosin plus tadalafil compared with tamsulosin alone (13 ± 17.0 vs −1.2 ± 14.35, P = 0.03). Moreover, Q_max increased in both treatment groups (1.0 ± 2.4 mL/s with tamsulosin + tadalafil and 1.4 ± 2.4 mL/s with tamsulosin + placebo), but differences were not significantly different (P = 0.65). Finally, LUTS/BPH decreased significantly in both the tadalafil plus tamsulosin and tamsulosin plus placebo groups (−9.75 vs −6.0 IPSS points, P = 0.01). No significant AEs led to discontinuation in the tadalafil plus tamsulosin group. This is the first trial – based on a computer-urodynamic study – to have demonstrated that tadalafil reduces detrusor pressure at maximum flow and improves LUTS/BPH without significantly changing Q_max.

Again in 2012, Yokoyama et al56 directly compared tadalafil with tamsulosin 0.2 mg in the first study to do so. The authors enrolled 612 men aged ≥ 45 years who had a history of LUTS/BPH for at least 6 months, a total IPSS ≥ 13, Q_max 4–15 mL/s, and a prostate volume > 20 mL. After a 2-week washout period and 4-week placebo lead-in period, they randomized patients into four groups and treated patients with once-daily placebo, tadalafil 2.5 mg, tadalafil 5 mg, or tamsulosin 0.2 mg for 12 weeks. From baseline to endpoint, LUTS/BPH significantly decreased by 4.8 IPSS points with tadalafil 2.5 mg (P = 0.003), 4.7 points with tadalafil 5 mg (P = 0.004), and 5.5 points with tamsulosin 0.2 mg compared with 3.0 IPSS points with placebo. They observed that a relevant decrease in total IPSS (P < 0.05) was reached after 2 weeks of once-daily tadalafil 5 mg treatment but only after 8 weeks for tadalafil 2.5 mg treatment. Q_max improvements were not significant with once-daily tadalafil or tamsulosin in this study. In terms of safety profile, the rate of discontinuation from each group due to AEs was 0.6% from the placebo group, 3.3% from the tadalafil 2.5 mg group, 4.5% from the tadalafil 5.0 mg group, and 1.3% from the tamsulosin group. In this study the authors demonstrated that tadalafil did not significantly modify prostate-specific antigen concentration during the 12-week treatment period (baseline to 12 weeks: 1.7 vs 1.8 ng/mL, P = 0.083).

Safety/tolerability and efficacy of tadalafil in systematic reviews and meta-analyses of men with LUTS/BPH

Safety

All PDE5-Is included in the systematic review authored by Liu et al57 showed a good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively). Moreover, the occurrence of serious AEs was rare for all PDE5-Is (1.1%, 1.85%, and 1.05% for the tadalafil, vardenafil, and sildenafil subgroups, respectively).

Martínez-Salamanca et al58 confirmed that tadalafil has a favorable tolerability profile, with most of the AEs being mild to moderate in severity. Moreover, discontinuation rates due to AEs were very low for tadalafil and comparable to those reported for placebo (2.0% vs 1.0%). Headache, dyspepsia, back pain, gastroesophageal reflux, sinusitis, and myalgia were the most frequently reported AEs in clinical trials (11.1%, 10.2%, 11.1%, 3.0%, 0.3%, and 5.7%, respectively; Table 1 ). These same AEs were reported in the previously published PDE5-I meta-analysis, however, the probability of an AE was higher in the latter report.2 The overall incidence of AEs reported in the present review on tadalafil versus placebo was very similar to that reported by Gacci et al2 in the systematic review of all PDE5-Is versus placebo: 16.0% versus 6.0%.

Table 1

The most common adverse events (AEs) reported for tadalafil in the different studies included in this review, n (%). Overall number of events for each drug and for each single AE are reported (%).

	Arm	McVary et al, 44 2007	Roehrborn et al,45 2008				Porst et al,48 2009				Dmochowski et al,50 2010	Porst et al,51 2011	Donatucci et al,52 2011	Oelke et al,53 2012	Yokoyama et al,55 2012	Overall
	Dose	10 mg	2.5 mg	5 mg	10 mg	20 mg	2.5 mg	5 mg	10 mg	20 mg	20 mg	5 mg	5 mg	5 mg	5 mg
Headache	D	4 (2.9)	5 (2.4)	6 (2.8)	11 (5.1)	7 (3.3)	4 (3.5)	4 (3.4)	6 (5.0)	2 (1.7)	3 (3.0)	6 (3.7)	0	5 (2.9)	3 (1.9)	66 (11.1)
	P	1 (0.7)	6 (2.8)	4 (3.5)	7 (7.1)	1(0.6)	3 (3.3)	2 (1.2)	1 (0.6)	25 (11.2)
Dyspepsia	D	6 (4.3)	2 (1.0)	10 (4.7)	6 (2.8)	10 (4.8)	1 (0.9)	5 (4.3)	2 (1.7)	3 (2.6)	8 (8.1)	4 (4.8)	4 (2.3)	61 (10.2)
	P	0	0	0	0	4(4.3)	0	4 (1.8)
Back pain	D	5 (3.6)	3 (1.4)	2 (0.9)	10 (4.6)	12 (5.7)	2 (1.8)	1 (0.9)	5 (4.2)	6 (5.2)	5 (5.1)	5 (3.1)	2 (2.4)	4 (2.3)	4 (2.6)	66 (11.1)
	P	2 (1.4)	1 (0.5)	1 (0.9)	3 (3.0)	4 (2.4)	4 (4.3)	1 (0.6)	1 (0.6)	17 (7.6)
G.E.Reflux	D	2 (1.0)	2 (0.9)	6 (2.8)	3 (1.4)	3 (3.0)	2 (2.4)	18 (3.0)
	P	0	0	2(2.2)	2 (0.9)
Sinusitis	D	2 (2.4)	2 (0.3)
	P	0	0
Rhinitis	D	3 (2.2)	7 (3.3)	4 (1.9)	2 (0.9)	5 (2.4)	5 (2.9)	2 (1.3)	2 (0.3)
	P	0	2 (0.9)	8 (4.7)	4 (2.6)	14 (6.3)
Hypertension	D	3 (3.6)	3 (0.5)
	P	0	0
Myalgia	D	3 (1.4)	3 (1.4)	6 (2.8)	6 (2.9)	2 (1.8)	1 (0.9)	4 (3.3)	3 (2.6)	6 (3.9)	34 (5.7)
	P	0	0	0	0
Cough	D	1 (1.2)	1 (0.2)
	P	1 (1.1)	1 (0.5)
Other	D	16 (11.2)	14	16	12	15	24	19	25	29	36	31	33	22	32	318 (53.2)
	P	3 (2.1)	5	19	18	31	36	24	24	160 (71.7)
Overall	D	28	36	43	53	58	33 (29.2)	30 (25.6)	42 (35.0)	43 (37.1)	55 (55.6)	42 (26.1)	47 (56.6)	40 (23.4)	47 (30.3)	597
	P	6	14	24 (20.9)	28 (27.7)	36 (22.0)	50 (54.3)	35 (20.3)	30 (19.5)	223

Abbreviations: D, drug; AE, adverse event; GE, gastroesophageal; P, placebo.

Efficacy

Liu et al57 included in their systematic review three studies (six RCTs) of tadalafil versus placebo, demonstrating a mean difference in IPSS change from baseline of 2.57 (95% confidence interval [CI] 3.15–1.98) and in IIEF-EF score of 5.34 (95% CI 4.11–6.57) in favor of tadalafil. In the same review, the meta-analysis of mean difference in Q_max and PVR were not statistically significant: 0.20 (95% CI 0.24–0.64, P = 0.38) and 0.47 (95% CI 5.17–6.10, P = 0.87), respectively. In this review, the authors emphasized that there is no significant correlation between LUTS/BPH improvement (change in IPSS) and recovery of sexual activity (change in IIEF-EF score) and that the efficacy of tadalafil on LUTS/BPH in men without ED demonstrates a direct activity of tadalafil on the LUT; in particular, the overall improvement of IPSS in men with ED overlapped the improvement in IPSS in men without ED (IPSS mean difference −2.57 vs −2.60, respectively).

In 2011, in a nonsystematic descriptive review including data from 1088 men treated with tadalafil compared with 444 treated with placebo, Martínez-Salamanca et al58 confirmed that tadalafil significantly improves LUTS/BPH compared with placebo (mean IPSS difference between treatments +4.2, P < 0.001). The overall decrease in IPSS was comparable with that reported in previous α-blocker studies. In the subgroup of sexually active men (55%), a significant improvement in EF was also reported (IIEF-EF domain scores +7.15 with tadalafil vs +2.38 with placebo, P = 0.001). Finally, none of the studies included in this review showed a significant effect of tadalafil on uroflowmetry variables.

The latest systematic review with meta-analysis by Gacci et al2 included four RCTs on tadalafil versus placebo (1360 vs 568 patients) and two RCTs on tadalafil plus α-blocker versus α-blocker alone (34 vs 32 patients). The overall outcomes in terms of efficacy as measured by IPSS, IIEF, and Q_max were very similar to those reported for other PDE5-Is selected for the review ( Figure 1 ). In particular, the most remarkable improvement in LUTS/BPH with tadalafil alone was obtained by Roehrborn et al’s study46 (mean difference in change from baseline compared with placebo: IPSS −3.7, CI −5.5 to −1.8), while the maximum improvement in LUTS/BPH achieved tadalafil and α-blocker combined therapy compared with α-blocker alone was reported by Bechara et al47 (IPSS −2.5, CI −5.7 to +0.7). Excellent results were obtained either with tadalafil alone or in combination with α-blockers with regard to EF (IIEF +6.8, CI 4.3–9.2 and IIEF +6.3, CI 0.9–11.7, respectively).45,47 Combination therapy with tadalafil and an α-blocker achieved a statistically significant – albeit clinically negligible – improvement of Q_max (+0.9 and +1.0 mL/s respectively).47,48 Moreover, Gacci et al’s2 meta-analysis demonstrated that younger men with lower BMI and more severe LUTS/BPH are the best candidates (target patients) for PDE5-I treatment when improvement of LUTS/BPH is intended.

Weighted mean differences (with 95% confidence interval) of International Prostate Symptom Score (IPSS) (A) and International Index of Erectile Function-Erectile Function (IIEF-EF) score (B) for the studies on tadalafil versus placebo.

Conclusion

Many preclinical and clinical studies emphasize the close link between LUTS/BPH and ED. The majority of active treatments for LUTS/BPH have a negative impact on EF.

The remarkable improvement of both LUTS/BPH and ED with tadalafil 5 mg once daily suggests a leading role for this PDE5-I treatment for men with comorbid BPH and ED. PDE5-I treatment is associated with a low rate of AEs and any AEs that do occur tend to be of low severity.

Further studies are needed to better understand the mechanisms of action of PDE5 or PDE5-Is, analyze the correct time for treatment, the cost-effectiveness of treatment, and to better define the long-term safety and efficacy of once-daily use of tadalafil 5 mg for men with LUTS/BPH with or without ED.

Footnotes

Matthias Oelke has been advisor, lecturer, or trial investigator for Eli Lilly and Company as well as for Pfizer. Mario Maggi is a scientific consultant for Bayer Pharma AG, Germany and Eli-Lilly Indianapolis, Indiana Other authors declare no conflicts of interest in this work.

References

1. Gacci M, Eardley I, Giuliano F, et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2011; 60 (4):809–825. [PubMed] [Google Scholar]

2. Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012; 61 (5):994–1003. [PubMed] [Google Scholar]

3. Macfarlane GJ, Botto H, Sagnier PP, Teillac P, Richard F, Boyle P. The relationship between sexual life and urinary condition in the French community. J Clin Epidemiol. 1996; 49 (10):1171–1176. [PubMed] [Google Scholar]

4. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999; 281 (6):537–544. [PubMed] [Google Scholar]

5. Blanker MH, Bohnen AM, Groeneveld FP, et al. Correlates for erectile and ejaculatory dysfunction in older Dutch men: a community-based study. J Am Geriatr Soc. 2001; 49 (4):436–442. [PubMed] [Google Scholar]

6. Li MK, Garcia LA, Rosen R. Lower urinary tract symptoms and male sexual dysfunction in Asia: a survey of ageing men from five Asian countries. BJU Int. 2005; 96 (9):1339–1354. [PubMed] [Google Scholar]

7. Brookes ST, Link CL, Donovan JL, McKinlay JB. Relationship between lower urinary tract symptoms and erectile dysfunction: results from the Boston Area Community Health Survey. J Urol. 2008; 179 (1):250–255. [PubMed] [Google Scholar]

8. Sak SC, Hussain Z, Johnston C, Eardley I. What is the relationship between male sexual function and lower urinary tract symptoms (LUTS)? Eur Urol. 2004; 46 (4):482–487. [PubMed] [Google Scholar]

9. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7) Eur Urol. 2003; 44 (6):637–649. [PubMed] [Google Scholar]

10. Wein AJ, Coyne KS, Tubaro A, Sexton CC, Kopp ZS, Aiyer LP. The impact of lower urinary tract symptoms on male sexual health: EpiLUTS. BJU Int. 2009; 103 (Suppl 3):33–41. [PubMed] [Google Scholar]

11. Bouwman II, Van Der Heide WK, Van Der Meer K, Nijman R. Correlations between lower urinary tract symptoms, erectile dysfunction, and cardiovascular diseases: are there differences between male populations from primary healthcare and urology clinics? A review of the current knowledge. Eur J Gen Pract. 2009; 15 (3):128–135. [PubMed] [Google Scholar]

12. Andersson KE, de Groat WC, McVary KT, et al. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action. Neurourol Urodyn. 2011; 30 (3):292–301. [PubMed] [Google Scholar]

13. Filippi S, Morelli A, Sandner P, et al. Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology. 2007; 148 (3):1019–1029. [PubMed] [Google Scholar]

14. Fibbi B, Morelli A, Vignozzi L, et al. Characterization of phosphodiesterase type 5 expression and functional activity in the human male lower urinary tract. J Sex Med. 2010; 7 (1 Pt 1):59–69. [PubMed] [Google Scholar]

15. Morelli A, Filippi S, Comeglio P, et al. Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats. J Sex Med. 2010; 7 (1 Pt 1):107–120. [PubMed] [Google Scholar]

16. Morelli A, Sarchielli E, Comeglio P, et al. Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats. J Sex Med. 2011; 8 (10):2746–2760. [PubMed] [Google Scholar]

17. Vignozzi L, Filippi S, Morelli A, et al. Cavernous neurotomy in the rat is associated with the onset of an overt condition of hypogonadism. J Sex Med. 2009; 6 (5):1270–1283. [PubMed] [Google Scholar]

18. Angulo J, Cuevas P, Fernández A, et al. Tadalafil enhances the inhibitory effects of tamsulosin on neurogenic contractions of human prostate and bladder neck. J Sex Med. 2012; 9 (9):2293–2306. [PubMed] [Google Scholar]

19. Morelli A, Filippi S, Sandner P, et al. Vardenafil modulates bladder contractility through cGMP-mediated inhibition of RhoA/Rho kinase signaling pathway in spontaneously hypertensive rats. J Sex Med. 2009; 6 (6):1594–1608. [PubMed] [Google Scholar]

20. Gacci M, Del Popolo G, Macchiarella A, et al. Vardenafil improves urodynamic parameters in men with spinal cord injury: results from a single dose, pilot study. J Urol. 2007; 178 (5):2040–2043. [PubMed] [Google Scholar]

21. Gacci M, Ierardi A, Rose AD, et al. Vardenafil can improve continence recovery after bilateral nerve sparing prostatectomy: results of a randomized, double blind, placebo-controlled pilot study. J Sex Med. 2010; 7 (1 Pt 1):234–243. [PubMed] [Google Scholar]

22. Fibbi B, Penna G, Morelli A, Adorini L, Maggi M. Chronic inflammation in the pathogenesis of benign prostatic hyperplasia. Int J Androl. 2010; 33 (3):475–488. [PubMed] [Google Scholar]

23. Gacci M, Vignozzi L, Sebastianelli A, et al. Metabolic syndrome and lower urinary tract symptoms: the role of inflammation. Prostate Cancer Prostatic Dis. 2012 Nov 20; Epub. [PubMed] [Google Scholar]

24. Kramer G, Mitteregger D, Marberger M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol. 2007; 51 (5):1202–1216. [PubMed] [Google Scholar]

25. Filippi S, Vignozzi L, Morelli A, et al. Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5 inhibitors in an animal model of male metabolic syndrome. J Sex Med. 2009; 6 (12):3274–3288. [PubMed] [Google Scholar]

26. Vignozzi L, Morelli A, Filippi S, et al. Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes. J Sex Med. 2011; 8 (1):57–77. [PubMed] [Google Scholar]

27. Vignozzi L, Morelli A, Sarchielli E, et al. Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. J Endocrinol. 2012; 212 (1):71–84. [PubMed] [Google Scholar]

28. Morelli A, Comeglio P, Filippi S, et al. Mechanism of action of phosphodiesterase type 5 inhibition in metabolic syndrome-associated prostate alterations: an experimental study in the rabbit. Prostate. 2012; 73 (4):428–441. [PubMed] [Google Scholar]

29. Morelli A, Comeglio P, Filippi S, et al. Testosterone and farnesoid X receptor agonist INT-747 counteract high fat diet-induced bladder alterations in a rabbit model of metabolic syndrome. J Steroid Biochem Mol Biol. 2012; 132 (1–2):80–92. [PubMed] [Google Scholar]

30. Maneschi E, Morelli A, Filippi S, et al. Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements. J Endocrinol. 2012; 215 (3):347–362. [PubMed] [Google Scholar]

31. Zenzmaier C, Sampson N, Pernkopf D, Plas E, Untergasser G, Berger P. Attenuated proliferation and trans-differentiation of prostatic stromal cells indicate suitability of phosphodiesterase type 5 inhibitors for prevention and treatment of benign prostatic hyperplasia. Endocrinology. 2010; 151 (8):3975–3984. [PubMed] [Google Scholar]

32. Penna G, Mondaini N, Amuchastegui S, et al. Seminal plasma cytokines and chemokines in prostate inflammation: interleukin 8 as a predictive biomarker in chronic prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia. Eur Urol. 2007; 51 (2):524–533. [PubMed] [Google Scholar]

33. McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol. 2011; 185 (5):1793–1803. [PubMed] [Google Scholar]

34. Hutchison A, Farmer R, Verhamme K, Berges R, Navarrete RV. The efficacy of drugs for the treatment of LUTS/BPH, a study in 6 European countries. Eur Urol. 2007; 51 (1):207–215. discussion 215–216. [PubMed] [Google Scholar]

35. Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol. 2002; 41 (5):497–506. [PubMed] [Google Scholar]

36. Zlotta AR, Teillac P, Raynaud JP, Schulman CC. Evaluation of male sexual function in patients with Lower Urinary Tract Symptoms (LUTS) associated with Benign Prostatic Hyperplasia (BPH) treated with a phytotherapeutic agent (Permixon), Tamsulosin or Finasteride. Eur Urol. 2005; 48 (2):269–276. [PubMed] [Google Scholar]

37. Chapple CR, Montorsi F, Tammela TL, Wirth M, Koldewijn E, Fernández Fernández E, European Silodosin Study Group Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011; 59 (3):342–352. [PubMed] [Google Scholar]

38. Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. CMAJ. 1996; 155 (9):1251–1259. [PMC free article] [PubMed] [Google Scholar]

39. Roehrborn CG, Siami P, Barkin J, et al.CombAT Study Group The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010; 57 (1):123–131. [PubMed] [Google Scholar]

40. McVary KT, Roehrborn CG, Avins AL, et al. American Urological Association Guideline: Management of BPH. Baltimore, MD; American Urological Association Education and Research; 2003. Guideline on the management of benign prostatic hyperplasia (BPH) [Google Scholar]

41. Bouza C, López T, Magro A, Navalpotro L, Amate JM. Systematic review and meta-analysis of Transurethral Needle Ablation in symptomatic Benign Prostatic Hyperplasia. BMC Urol. 2006; 6 :14. [PMC free article] [PubMed] [Google Scholar]

42. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms, including benign prostatic obstruction. Eur Urol. 2013 [Epub ahead of print. March 2013] [PubMed] [Google Scholar]

43. Roehrborn CG. Standard surgical interventions: TURP/TUIP/OPSU. In: Kirby RS, McConnell JD, Fitzpatrick JM, Roehrborn CG, Boyle P, editors. Textbook of Benign Prostatic Hyperplasia. Oxford; ISIS Medical Media; 1996. pp. 341–378. [Google Scholar]

44. Briganti A, Naspro R, Gallina A, et al. Impact on sexual function of holmium laser enucleation versus transurethral resection of the prostate: results of a prospective, 2-center, randomized trial. J Urol. 2006; 175 (5):1817–1821. [PubMed] [Google Scholar]

45. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007; 177 (4):1401–1407. [PubMed] [Google Scholar]

46. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008; 180 (4):1228–1234. [PubMed] [Google Scholar]

47. Bechara A, Romano S, Casabé A, et al. Comparative efficacy assessment of tamsulosin vs tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot study. J Sex Med. 2008; 5 (9):2170–2178. [PubMed] [Google Scholar]

48. Liguori G, Trombetta C, De Giorgi G, et al. Efficacy and safety of combined oral therapy with tadalafil and alfuzosin: an integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. Preliminary report. J Sex Med. 2009; 6 (2):544–552. [PubMed] [Google Scholar]

49. Porst H, McVary KT, Montorsi F, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol. 2009; 56 (4):727–735. [PubMed] [Google Scholar]

50. Roehrborn CG, Kaminetsky JC, Auerbach SM, Montelongo RM, Elion-Mboussa A, Viktrup L. Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment. BJU Int. 2010; 105 (4):502–507. [PubMed] [Google Scholar]

51. Dmochowski R, Roehrborn C, Klise S, Xu L, Kaminetsky J, Kraus S. Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized, placebo controlled 12-week clinical trial. J Urol. 2010; 183 (3):1092–1097. [PubMed] [Google Scholar]

52. Porst H, Kim ED, Casabé AR, et al.LVHJ study team Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol. 2011; 60 (5):1105–1113. [PubMed] [Google Scholar]

53. Donatucci CF, Brock GB, Goldfischer ER, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int. 2011; 107 (7):1110–1116. [PubMed] [Google Scholar]

54. Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol. 2012; 61 (5):917–925. [PubMed] [Google Scholar]

55. Regadas RP, Reges R, Cerqueira JB, et al. Urodynamic effects of the combination of tamsulosin and daily tadalafil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: a randomized, placebo-controlled clinical trial. Int Urol Nephrol. 2012; 45 (1):39–43. [PubMed] [Google Scholar]

56. Yokoyama O, Yoshida M, Kim SC, et al. Int J Urol. 2012. Sep 7, 2012. Tadalafil once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a randomized placebo- and tamsulosin-controlled 12-week study in Asian men. Epub. [PubMed] [Google Scholar]

57. Liu L, Zheng S, Han P, Wei Q. Phosphodiesterase-5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a systematic review and meta-analysis. Urology. 2011; 77 (1):123–129. [PubMed] [Google Scholar]

58. Martínez-Salamanca JI, Carballido J, Eardley I, et al. Phosphodiesterase type 5 inhibitors in the management of non-neurogenic male lower urinary tract symptoms: critical analysis of current evidence. Eur Urol. 2011; 60 (3):527–535. [PubMed] [Google Scholar]

Tadalafil Tablets (Erectile Dysfunction, BPH)

TADALAFIL (tah DA la fil) treats erectile dysfunction (ED). It works by increasing blood flow to the penis, which helps to maintain an erection. It may also be used to treat symptoms of an enlarged prostate (benign prostatic hyperplasia).

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

COMMON BRAND NAME(S): Adcirca, ALYQ, Cialis

What should I tell my care team before I take this medication?

They need to know if you have any of these conditions:

How should I use this medication?

Take this medication by mouth with a glass of water. Follow the directions on the prescription label. You may take this medication with or without meals. When this medication is used for erection problems, your care team may prescribe it to be taken once daily or as needed. If you are taking the medication as needed, you may be able to have sexual activity 30 minutes after taking it and for up to 36 hours after taking it. Whether you are taking the medication as needed or once daily, you should not take more than one dose per day. If you are taking this medication for symptoms of benign prostatic hyperplasia (BPH) or to treat both BPH and an erection problem, take the dose once daily at about the same time each day. Do not take your medication more often than directed.

Talk to your care team about the use of this medication in children. Special care may be needed.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.

NOTE: This medicine is only for you. Do not share this medicine with others.

What if I miss a dose?

If you are taking this medication as needed for erection problems, this does not apply. If you miss a dose while taking this medication once daily for an erection problem, benign prostatic hyperplasia, or both, take it as soon as you remember, but do not take more than one dose per day.

What may interact with this medication?

Do not take this medication with any of the following:

This medication may also interact with the following:

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medication?

If you notice any changes in your vision while taking this medication, call your care team as soon as possible. Stop using this medication and call your care team right away if you have a loss of sight in one or both eyes.

Contact your care team right away if the erection lasts longer than 4 hours or if it becomes painful. This may be a sign of serious problem and must be treated right away to prevent permanent damage.

If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medication, you should refrain from further activity and call your care team as soon as possible.

Do not drink alcohol to excess (examples, 5 glasses of wine or 5 shots of whiskey) when taking this medication. When taken in excess, alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate or lowering your blood pressure.

Using this medication does not protect you or your partner against HIV infection (the virus that causes AIDS) or other sexually transmitted diseases.

What side effects may I notice from receiving this medication?

Side effects that you should report to your care team as soon as possible:

Side effects that usually do not require medical attention (report to your care team if they continue or are bothersome):

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medication?

Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Throw away any unused medication after the expiration date.

NOTE: This sheet is a summary. It may not cover all possible information. If you have questions about this medicine, talk to your doctor, pharmacist, or health care provider.

Cialis Dosage Guide: What Is The Right Dosage?

If you live with erectile dysfunction (ED), you’ve probably heard about the drug Cialis® and its potential for helping you get and maintain an erection.

Cialis, which is also available as the generic medication tadalafil, has been proven effective at managing ED in men.

But more than that, its long half-life allows for some flexibility in sexual intercourse that other ED medications don’t offer.

Cialis is available in four different doses that cover all of the bases. There are daily dosages of 2.5mg and 5 mg, which allow for spontaneous sexual activity.

It’s also available in 10mg and 20mg dosages, which can be taken as-needed to treat ED and allow you to have sex when you want to.

This dosage gives you the choice of taking Cialis just before sex, without having to use medication every day.

Used as-needed, one dosage of Cialis can last for up to 36 hours, saving you the need to plan ahead like with shorter-acting medications such as sildenafil (the active ingredient in Viagra®), vardenafil (Levitra®) or avanafil (Stendra®).

But with all of these options to choose from, you’re probably wondering which dosage of Cialis might be right for you.

Let us help in making your decision easier. We’ll start at the beginning by explaining how Cialis works as a treatment for erectile dysfunction.

Then, we’ll look at the dosages that are available to help you determine which is the best option for you.

What Is Cialis (Tadalafil) Used For?

Tadalafil, the active ingredient in Cialis, is used to treat a handful of different conditions. While it is best known as a treatment for erectile dysfunction, it’s also used to treat:

Benign prostatic hyperplasia (BPH, or enlarged prostate)

We’ve discussed the different uses of Cialis below, as well as how the medication works to treat these conditions.

Cialis for Erectile Dysfunction

Cialis is best known as a treatment for erectile dysfunction. Like other ED medications, it works by inhibiting the effects of an enzyme called PDE5, which is responsible for controlling the flow of blood to your penis.

Healthy erections are all about blood flow. When you feel sexually aroused, blood flows to your corpora cavernosa — the soft, sponge-like erectile tissue that’s inside your penis — causing it to become firm and enlarged.

Medications that reduce the effects of PDE5 are referred to as PDE5 inhibitors. By inhibiting the effects of PDE5, medications such as Cialis relax and expand the blood vessels near the penis and increase blood flow, allowing for easier, more reliable erections.

Cialis for Benign Prostatic Hyperplasia (BPH)

Although Cialis is usually thought of as a medication for ED, it’s also used to treat several other conditions.

One of these is benign prostatic hyperplasia — a condition in which the prostate gland grows in size. BPH is also commonly referred to as benign prostate enlargement, or simply as enlarged prostate.

BPH is common in older men. Although it isn’t a cancerous form of growth, it can cause certain irritating symptoms, such as an increased need to urinate, dribbling at the end of urination and pain during urination or after ejaculation.

Cialis for Pulmonary Arterial Hypertension (PAH)

Tadalafil, the active ingredient in Cialis, is also used to treat pulmonary arterial hypertension, a form of pulmonary hypertension in which blood pressure increases in the arteries that transport blood from your heart to your lungs.

Pulmonary arterial hypertension can develop on its own or with other cardiovascular diseases, such as left heart disease (LHD), sickle cell disease (SCD) and its variants, chronic obstructive pulmonary disease (COPD) and conditions such as pulmonary embolism (PE).

Tadalafil and other PDE5 inhibitors treat PAH by dilating the arteries inside the lungs, reducing blood pressure and improving blood flow.

When it’s used to treat pulmonary arterial hypertension, tadalafil is usually sold under the brand name Adcirca®. To learn more, read our blog on Adcirca vs. Cialis.

How Does Cialis Help You Last Longer in Bed?

A variety of different things can contribute to or cause erectile dysfunction, but many of the most common are physical health issues that affect blood flow.

By dilating the blood vessels that supply blood to your penis, Cialis and similar medications help to promote firmer, healthier erections.

This is important if you find it difficult to develop an erection, but it’s also important if you can get an erection, but often lose it during sex.

ED can vary in severity. For some guys, it can mean a total inability to get an erection, even with sexual stimulation.

For others, it might mean getting an erection but finding it difficult to maintain it during sex, or not being able to get an erection every time you want to have sex.

Because of its effects on blood flow to your penis, Cialis has a positive effect on your erections, as well as your general sexual function.

For example, some research has found that Cialis may help to increase ejaculation latency time (the amount of time that passes before reaching orgasm and ejaculating).

genuine cialis has your back all weekend

Dosages of Cialis

Since ED can vary in severity based on many different factors, right off the bat, you should know that there’s no uniform dosage of Cialis that will work for everyone.

The most appropriate Cialis dose for you will depend on your needs, your healthcare provider’s assessment and how well you respond to the medication.

Cialis is available in two forms — as a daily-use medication, and for use as-needed. Daily Cialis is available in dosages of 2.5mg and 5mg.

If you’re prescribed Cialis for daily use, it’s important to take it at approximately the same time every day.

Taking Cialis every day is a good option if you’ve already responded well to PDE5 inhibitors, or if you have sex more than two times per week.

Most of the time, your healthcare provider will prescribe Cialis for daily use at a daily dosage of 2.5mg.

This may be increased to 5mg if you don’t respond to the lower dosage, or if you need a more significant effect from the medication.

Cialis is also available as-needed. This means that you take this medication whenever you plan to have sex within a day.

When prescribed for as-needed use, Cialis is available in 5mg, 10mg and 20mg doses.

The recommended starting dose of Cialis for use as needed is 10mg. This may be increased to 20mg if you still find it difficult to get or maintain an erection at a 10mg dose, or reduced to 5mg if you develop side effects from Cialis.

Cialis is designed for use one time per day. Regardless of the Cialis dosage you’re prescribed, you should not take Cialis or other ED medication more than once per day.

Like other medications for ED, Cialis starts working quickly. In most cases, you’ll start to notice the effects of Cialis in 30 to 60 minutes.

Cialis reaches its maximum concentration in your body approximately 30 minutes to six hours after use.

Cialis absorption is not affected by food, meaning you can take Cialis on its own or with a meal without affecting the amount of time it takes for the medication to start working.