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A review of the use of tadalafil in the treatment of benign prostatic hyperplasia in men with and without erectile dysfunction

Epidemiological data link erectile dysfunction (ED) and benign prostatic hyperplasia (BPH)-associated lower urinary tract symptoms (LUTS), two highly prevalent conditions in aging men, assuming common pathophysiological pathways. Tadalafil 5 mg once daily has been approved for the treatment of men with LUTS with or without comorbid ED. The aim of this review is to provide an overview of current knowledge on the epidemiological and pathophysiological links between ED and LUTS and to focus on tadalafil as a new treatment option in men with BPH-associated LUTS.

A Medline search was completed using the Medical Subject Headings (MESH® keywords) ‘prostatic hyperplasia’ and ‘phosphodiesterase inhibitors’. This search revealed 125 relevant references (entire Medline database up to 11 March 2014). The efficacy of tadalafil 5 mg once daily for the treatment of LUTS has been reported by several well-designed studies. Tadalafil improves significantly the total International Prostate Symptom Score (IPSS), the voiding and storage subscores, the IPSS Quality of Life (QoL) and the BPH Impact Index (BII). Its efficacy is irrelevant to the erectile function status of the patients. However, in the majority of these studies tadalafil is not associated with improvement in maximum urine flow or post-void residual volume (PVR). Its safety profile is well established and no new or unexpected adverse events other than those reported in ED studies have been recorded. Tadalafil is today a new treatment alternative to other established drugs for LUTS such as the α-adrenergic antagonists or 5α-reductase inhibitors. However, it is not just an alternative, since sexual adverse events associated with these drugs are avoided and tadalafil is the only drug that can treat both ED and LUTS at the same time.

Keywords: erectile dysfunction, lower urinary tract symptoms, phosphodiesterase inhibitors, prostatic hyperplasia

Introduction

Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) are highly prevalent conditions associated with a significant negative impact on patients’ quality of life [Rosen et al. 2003, Robertson et al. 2007]. For a long time, ED and LUTS were considered to be two distinct clinical entities with an increasing prevalence in aging men despite the fact that almost all treatment modalities for benign prostatic hyperplasia (BPH)-associated LUTS have some negative impact on patients’ sexual function [Gacci et al. 2011]. This common belief has been rejected by several epidemiological studies showing a strong relationship between them and that they share several comorbidities and lifestyle factors [Rosen et al. 2005; Roehrborn et al. 2007]. While it is not clear how they are associated, there are emerging data supporting common pathophysiological mechanisms [McVary, 2005].

Phosphodiesterase type 5 inhibitors (PDE5i) are the current first-line treatment option for the majority of men with ED due to their excellent efficacy and safety profile [Hatzimouratidis et al. 2010]. Early clinical research showed that all PDE5i are also beneficial for the treatment of LUTS [McVary et al. 2007a, 2007b; Stief et al. 2008]. However, only tadalafil 5 mg once daily has been approved for the treatment of BPH-associated LUTS in men with or without ED. These new data provided new treatment options in the urologic armamentarium but also further promoted clinical research aiming to better understand the pathophysiology of LUTS.

The aim of this review is to provide an update on the current knowledge on the rationale for the use of tadalafil for the treatment of BPH-associated LUTS, and its efficacy and safety. A Medline (http://www.ncbi.nlm.nih.gov) search was completed using the Medical Subject Headings (MESH® keywords) ‘prostatic hyperplasia’ and ‘phosphodiesterase inhibitors’ in the English language only. This search revealed 125 relevant references (entire Medline database up to 11 March 2014).

The rationale for the use of tadalafil in the treatment of BPH-associated LUTS

Epidemiological data on the association of ED and LUTS

Several epidemiological studies have reported a strong correlation between ED and LUTS. The National Health and Social Life Survey (NHSLS) [Laumann et al. 1999] demonstrated an increasing prevalence of ED in men with age, ranging from 7% to 18%. In the Cologne Male Survey [Braun et al. 2000, 2003] the overall prevalence of ED was 19.2%. The EDEM study [Martin-Morales et al. 2001] reported an ED prevalence rate of 12.1%. The Krimpen study [Blanker et al. 2001a, 2001b] showed that the overall prevalence of significant (severe) ED was 11%. The UrEpik study [Boyle et al. 2003] reported that the overall prevalence of ED was 21%. The Cross National Study on the Epidemiology of ED and its Correlates [Nicolosi et al. 2003a, 2003b] reported an overall prevalence of moderate or complete ED of 16%. The Multinational Survey of the Aging Male (MSAM-7) [Rosen et al. 2003] reported an overall prevalence of ED (difficulty achieving an erection) of 48.7% with 10% of men reporting complete absence of erections. In a population-based study in Denmark, the prevalence of ED was 28.8% while the prevalence of LUTS was 39.1% [Hansen, 2004]. Finally, in the Boston Area Community Health (BACH) study [Brookes et al. 2008] the overall prevalence of ED was 47% (less than 10% reported moderate or severe dysfunction) while the overall prevalence of LUTS was 81% (only 19% reported moderate or severe symptoms). In all of these studies LUTS were a significant risk factor for ED, but in the majority of them, LUTS were also an independent risk factor [Blanker et al. 2001; Braun et al. 2003; Nicolosi et al. 2003a; Rosen et al. 2003; Hansen, 2004]

These studies can be criticized due their cross-sectional design which cannot address the temporal relationship between LUTS and ED. Therefore, it is not possible to establish a definite causal association between LUTS and ED. There are only two longitudinal, prospective studies assessing the causal relationship between LUTS and ED. Shiri and colleagues [Shiri et al. 2005b], in a population-based study in Tampere (Finland), reported that the 5-year incidence of ED was greater in men reporting LUTS at baseline. Compared with men with no LUTS (IPSS: 0), the incidence of ED was 2.7 times higher among men with IPSS 7–11, and 3.1 times higher in men with IPSS 12 or more. Men with mild bother scores were at higher risk of ED than those with mild symptoms scores [Shiri et al. 2005a] while the incidence of LUTS was higher in men with moderate or severe ED than in those free of ED at baseline [Shiri et al. 2007]. In the Health Professionals Follow-Up Study (HPFS) [Mondul et al. 2008], men with severe LUTS in 1994 or earlier had a statistically significant 40% higher risk of ED subsequently compared with men without LUTS when assessed in year 2000. The risk of ED increased with increasing LUTS severity and the positive association between LUTS and ED was stronger in younger than in older men.

Common pathophysiological pathways

While the common pathophysiological pathways between ED and LUTS are not clear, four theories have been described and reviewed in the literature [McVary, 2005; Ponholzer and Madersbacher, 2007; Kohler and McVary, 2009; Gacci et al. 2011]. The first hypothesis includes impaired nitric oxidase synthase (NOS) in the endothelium of the pelvis including the prostate, bladder and penis. The second hypothesis is based on increased Rho-kinase activation resulting in decreased smooth muscle relaxation with consecutive increased bladder outlet resistance and impaired erection. The third hypothesis is based on the autonomic hyperactivity and metabolic syndrome effects on LUTS, prostate growth and ED. Finally, the fourth hypothesis illustrates atherosclerosis as a common mechanism for LUTS and ED. These theories are compatible and may overlap substantially [Kohler and McVary, 2009]. The theories of impaired NOS and reduced NO levels, increased Rho-kinase activation and atherosclerosis and pelvic ischemia are linked by common vascular risk factors. Atherosclerosis may reduce NO levels and Rho-kinase activation and may result in loss of smooth muscle from the bladder detrusor and prostate fibrosis associated with loss of bladder compliance and increased urethral resistance, respectively.

What is the evidence on tadalafil based on these four theories? The upregulation of the NO/cGMP activity is probably the most important. Preclinical studies reported partial reversal of norepinephrine- and endothelin-1-reduced prostatic tissue contraction [Kedia et al. 2009] and an antiproliferative effect on cultured prostate and bladder smooth muscle cells [Filippi et al. 2007]. These mechanisms may decrease smooth muscle tension in the prostatic stroma and capsule and attenuate cellular proliferation associated with prostate/bladder hypertrophy, respectively. An assessment of the activity of PDE5i on endothelin-1-induced contraction of human prostatic tissue (mediated by ROCK pathway) showed that tadalafil had greater activity when compared with sildenafil or vardenafil and among PDE5i, only tadalafil achieved >50% relaxation of the precontracted strips [Kedia et al. 2009]. Evidence on the efficacy of tadalafil in the modulation of autonomic nervous system overactivity and afferent nerve activity is very limited. PDE5i cause an inhibitory effect of NO on ion channels in afferent neurons and on afferent nerve activity in the bladder. Calcium channels in bladder afferent neurons are inhibited by NO [Yoshimura et al. 2001]. Moreover, vardenafil reduces nonvoiding contractions associated with bladder afferent nerve firing [Behr-Roussel et al. 2011]. Tadalafil inhibits in vitro PDE5 activity, prominently expressed in the human vesicular-deferential arteries and increases prostate tissue oxygenation in spontaneously hypertensive rats [Morelli et al. 2011]. Moreover, tadalafil increased prostatic blood perfusion in a preliminary evaluation of men using contrast-enhanced ultrasound [Bertolotto et al. 2009]. Finally, tadalafil attenuates the expression of various inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-1β and IL-8) and therefore may reduce atherosclerotic damage and overall inflammation by reducing leukocyte recruitment [Roumeguere et al. 2010]. Tadalafil’s proposed mechanism of action based on current data is presented in Figure 1 [Andersson et al. 2011].

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Mechanisms by which tadalafil may reduce benign prostatic hyperplasia (BPH)-associated lower urinary tract symptoms.

Clinical data on the efficacy and safety of tadalafil in men with BPH-associated LUTS

Efficacy data of PDE5i in the treatment of LUTS

McVary and colleagues [McVary et al. 2007b] reported on the first double-blind, placebo-controlled trial with tadalafil in men with both ED and LUTS. A total of 281 men were randomized in a 1:1 ratio to receive 5 mg of tadalafil daily (138 men, mean age: 61 years) followed by dose escalation to 20 mg for 6 weeks or 12 weeks of placebo (143 men, mean age: 62 years). Tadalafil significantly improved the mean change from baseline in IPSS at 6 weeks (5 mg tadalafil −2.8 versus placebo -1.2) and at 12 weeks (5/20 mg tadalafil −3.8 versus placebo −1.7). Larger changes were observed with inclusion of the placebo run-in at 12 weeks (5/20 mg tadalafil −7.1 versus placebo −4.5). Mean irritative and obstructive IPSS subscores, the IPSS QoL index, a question about urinary symptom improvement and the BPH Impact Index (BII) significantly improved versus placebo. IPSS and International Index of Erectile Function (IIEF) scores significantly improved in the 56% of men with LUTS who were sexually active and had ED. No differences in uroflowmetry parameters were recorded in the placebo and tadalafil groups. Moreover, no change in PVR was recorded in the tadalafil group.

Porst and colleagues [Porst et al. 2009] reported on the efficacy of tadalafil in a subset of patients included in the previous study with ED. Overall, 581 men were included (115 in the placebo group, 113 in the tadalafil 2.5 mg group, 117 in the tadalafil 5 mg group, 120 in the tadalafil 10 mg group and 116 in the tadalafil 20 mg group). IPSS improvements from baseline to end point with tadalafil were −3.6 (2.5 mg), −4.2 (5 mg), −4.7 (10 mg) and −4.7 (20 mg) versus −2.1 with placebo (all p values < 0.05). Similarly, the changes in peak urinary flow (Qmax) and PVR were small and not clinically meaningful. Therefore, the efficacy of tadalafil in the treatment of BPH-associated LUTS is similar in men with or without ED. In this context, Broderick and colleagues [Broderick et al. 2010] reported on another paper again based on the same database of patients that changes in BPH–LUTS after 12 weeks of treatment with placebo or various doses of once-daily tadalafil were similar in men with or without comorbid ED. After 12 weeks, changes in IPSS in men with ED (change from baseline, placebo −2.4; tadalafil 2.5, 5, 10, 20 mg −4.3, −4.8, −5.3, −5.6) and without ED (−2.4, −3.2, −5.3, −5.1, −4.5) were not significantly different (subgroup/interaction p values: 0.352/0.644). Similar effects were observed for IPSS QoL (with ED: −0.6, −0.9, −0.9, −1.0, −1.1; without ED: −0.6, −0.7, −0.9, −0.8, −0.8; 0.090/0.773) and BII (with ED: −0.7, −0.9, −1.3, −1.3, −1.4; without ED: −1.0, −0.7, −1.3, −1.3, −1.2; 0.753/0.852).

Porst and colleagues [Porst et al. 2011] reported also on the efficacy of tadalafil 5 mg versus placebo in a randomized, double-blind, placebo-controlled, 12-week study including 325 men with BPH-associated LUTS. Tadalafil 5 mg significantly improved IPSS versus placebo (−5.6 versus −3.6; p = 0.004) and this improvement was apparent after 1 week and significant after 4 weeks (−5.3 versus −3.5; p = 0.003). The BII improvement was apparent at 4 weeks (−1.8 versus −1.2; p = 0.029) and continued at 12 weeks (−1.8 versus −1.3; p = 0.057). Tadalafil 5 mg significantly improved the IIEF erectile function domain score in sexually active men with ED (6.7 versus 2.0; p < 0.001) at 12 weeks. Finally, tadalafil 5 mg did not significantly improve Qmax or PVR.

Recently, three papers provided analysis of pooled data from four randomized, double-blind, placebo-controlled, 12-week, parallel-design, multinational LUTS/BPH studies assessing the efficacy and safety of tadalafil once-daily for LUTS/BPH [Roehrborn et al. 2008; Porst et al. 2011; Oelke et al. 2012] or LUTS/BPH and ED [Egerdie et al. 2012].

Porst and colleagues [Porst et al. 2013b] reported that tadalafil significantly improved total IPSS versus placebo (mean changes −6.0 and −3.6, respectively; p 0.001). Improvements in the IPSS storage and voiding subscores, IPSS QoL, BII and the IIEF erectile function domain score were also significant versus placebo (all p 0.001). Nonsignificant impact of baseline ED severity or PSA category on IPSS response was observed (interaction p values, 0.463 and 0.149, respectively) while the IIEF erectile function domain score was not significantly impacted by baseline LUTS/BPH severity or PSA category (interaction p values, 0.926 and 0.230, respectively). Finally, improvements in IPSS and IIEF scores during treatment were weakly correlated (r = −0.229).

Porst and colleagues [Porst et al. 2013a] also presented subgroup analyses demonstrating that IPSS improvements were significant regardless of baseline LUTS severity (IPSS 65 years), recent previous use of α-adrenergic antagonists or PDE5i, total testosterone level (40 ml). The rates of treatment emergent adverse events were comparable between all subgroups but were somewhat higher in patients with recent previous α-adrenergic antagonists use.

Finally, Brock and colleagues [Brock et al. 2013] reported that tadalafil significantly reduced BPH-associated LUTS compared with placebo in men without ED (IPSS −5.4 versus −3.3, p 0.01; IPSS voiding subscore −3.5 versus −2.0, p 0.01; IPSS storage subscore −1.9 versus −1.3, p 0.05). Tadalafil also significantly improved QoL (IPSS QoL −1.0 versus −0.7; BII −1.4 versus −1.0; both p 0.05).

Based on these analyses of the pooled data the improvements of tadalafil in IPSS, IPSS storage and voiding subscores, BII and IPSS QoL in all patients and in patients stratified by their erectile function status are presented in Figures 2 , ​ ,3, 3 , ​ ,4, 4 , ​ ,5 5 and ​ and6, 6 , respectively [Brock et al. 2013; Porst et al. 2013b.

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Improvement in International Prostate Symptom Score (IPSS) in all patients treated with tadalafil 5 mg versus placebo (p < 0.001), in patients without erectile dysfunction (ED; p < 0.05) and in patients with ED (p < 0.001). Improvement was similar between men without ED and with ED (p value for treatment-by-ED-status interaction was insignificant for total IPSS, p = 0.73). Data from Brock et al. [2013] and Porst et al. [2013b].

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Improvement in International Prostate Symptom Score (IPSS) storage subscore in all patients treated with tadalafil 5 mg versus placebo (p < 0.001), in patients without erectile dysfunction (ED; p < 0.05) and in patients with ED (p < 0.001). Improvement was similar between men without ED and with ED (p value for treatment-by-ED-status interaction was insignificant for IPSS storage subscore, p = 0.78). Data from Brock et al. [2013] and Porst et al. [2013b].

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Improvement in International Prostate Symptom Score (IPSS) voiding subscore in all patients treated with tadalafil 5 mg versus placebo (p < 0.001), in patients without erectile dysfunction (ED; p < 0.05) and in patients with ED (p < 0.001). Improvement was similar between men without ED and with ED (p value for treatment-by-ED-status interaction was insignificant for IPSS voiding subscore, p = 0.69). Data from Brock et al. [2013] and Porst et al. [2013b].

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Improvement in International Prostate Symptom Score (IPSS) quality of life (QoL) subscore in all patients treated with tadalafil 5 mg versus placebo (p < 0.001), in patients without erectile dysfunction (ED; p < 0.05) and in patients with ED (p < 0.001). Improvement was similar between men without ED and with ED (p value for treatment-by-ED-status interaction was insignificant for IPSS QoL, p = 0.89). Data from Brock et al. [2013] and Porst et al. [2013b].

Finally, Brock and colleagues [Brock et al. 2014] using unidirectional and bidirectional path analysis models reported that tadalafil 5mg once daily directly improved urinary tract symptoms secondary to BPH regardless of underlying ED. Therefore, tadalafil’s effect is not due to indirect effects including psychological benefits of improved erectile function in men with both conditions.

Analysis and interpretation of the urodynamic data

Despite the fact that all placebo-controlled trials showed clearly a positive effect on LUTS including both obstructive and irritative scores and QoL scores, none of these studies shows any efficacy in terms of uroflowmetry parameters (Qmax) or PVR. These parameters are considered an important outcome measure in clinical trials, assessing the impact of drugs on LUTS including α-adrenergic receptor antagonists and 5α-reductase inhibitors.

Following the dose-finding study, Roehrborn and colleagues [Roehrborn et al. 2010], provided a post hoc analysis on the effects of tadalafil on Qmax, bladder capacity (voided urine plus PVR) and voiding efficiency (voided urine/bladder capacity). None of these parameters improved statistically significant. Tadalafil had its greatest effects on bladder capacity and voiding efficiency in men with a Qmax of

Dmochowski and colleagues [Dmochowski et al. 2010] presented data from a 12-week, multicenter, randomized, double-blind, placebo-controlled clinical trial comparing tadalafil 20 mg once daily versus placebo in men with BPH-associated LUTS. Invasive and noninvasive urodynamics were done in order to identify the possible effect of tadalafil at its maximal dose in the lower urinary tract system. Urodynamic measures remained largely unchanged during the study with no statistically significant or clinically adverse difference between tadalafil and placebo in change in detrusor pressure at maximum urinary flow rate (mean difference between treatments −2.2 cm H2O, p = 0.33) or any other urodynamic parameter assessed including maximum urinary flow rate, maximum detrusor pressure, bladder outlet obstruction index or bladder capacity (all measures p ≥ 0.13) despite the fact that tadalafil significantly improved IPSS.

A recent meta-analysis [Dong et al. 2013] reported that after pooling four doses (2.5, 5, 10 and 20 mg), tadalafil failed to produce a significant outcome in Qmax although it was improved (mean difference = +0.26 ml/s, p = 0.14), but 5 mg of tadalafil significantly improved Qmax (mean difference = +0.63 ml/s, p = 0.04).

Is there any explanation for these findings? The answer is currently no. McVary commented that it might be a potential new basic pathophysiology paradigm in which the impact of PDE5 activity on LUTS symptoms may reveal an alternate explanation for the etiology of LUTS not involving relaxation of prostatic smooth muscle but bladder compliance changes, improvement in bladder wall perfusion or central nervous system impact [McVary, 2006]. While the answer to this question is of the highest importance in understanding the mechanisms of LUTS and the effect of new treatments, its importance from a clinical point of view may be less significant since symptom alleviation is the primary treatment target in the majority of patients.

Long-term efficacy of tadalafil

While the efficacy of tadalafil was established from placebo-controlled studies, it is unknown whether this positive effect is maintained through time. This is important to know since LUTS are a chronic condition and treatments must be efficacious also in the long-term. In this context, Donatucci and colleagues [Donatucci et al. 2011] reported on the long-term efficacy of tadalafil. A total of 427 men who completed the 12-week, placebo-controlled, dose-finding study assessing once-daily tadalafil (2.5, 5, 10 or 20 mg) or placebo elected to continue into the open-label extension period using tadalafil 5 mg. Changes in the total IPSS, IPSS irritative and obstructive subscores, IPSS health-related QoL and BII were maintained after 1 year and were similar despite the tadalafil dose administered during the double-blind study. During the open-label extension period, mean PSA increased from 1.6 ± 1.3 to 1.8 ± 1.4 ng/ml. Mean PVR was 61.1 ± 60.4 ml at study entry and 42.2 ± 64.1 ml after the open-label extension period. Therefore, it can be concluded that the efficacy of tadalafil is maintained for at least 1 year.

Comparative data on the efficacy of tadalafil and tamsulosin

Another important question that rises up is the efficacy of tadalafil compared with an established treatment for BPH-associated LUTS such as an α-adrenergic antagonist. In this context, Oelke and colleagues [Oelke et al. 2012], reported on a randomized, double-blind, international, placebo-controlled, parallel-group study including tamsulosin as an active control. A total of 511 men with BPH/LUTS were randomized to placebo (n = 172), tadalafil 5 mg (n = 171) or tamsulosin 0.4 mg (n = 168) once daily for 12 weeks following a 4-week run-in period. This study was not designed for statistical testing of noninferiority or superiority between tadalafil and tamsulosin but it was adequately powered for the comparison of each active treatment with placebo. IPSS scores significantly improved versus placebo with tadalafil (−2.1; p = 0.001) and tamsulosin (−1.5; p = 0.023). This improvement was evident as early as 1 week (tadalafil and tamsulosin both −1.5; p < 0.01). BII significantly improved versus placebo (tadalafil −0.8, p = 0.003; tamsulosin −0.6, p = 0.026). The IPSS QoL index and the Treatment Satisfaction Scale-BPH improved significantly versus placebo with tadalafil (both p < 0.05) but not with tamsulosin (both p > 0.1). Surprisingly, given the data from previously published studies, Qmax increased significantly versus placebo with both tadalafil (2.4 ml/s; p = 0.009) and tamsulosin (2.2 ml/s; p = 0.014). PVR decrease was higher with tamsulosin but statistical significance was not reached by either treatment versus placebo.

As expected, the IIEF erectile function domain improved versus placebo with tadalafil (4.0; p < 0.001) but not tamsulosin (−0.4; p = 0.699). Giuliano and colleagues [Giuliano et al. 2013], reported on the effects of tadalafil or tamsulosin on sexual function, including ejaculation and orgasm, satisfaction and erectile function based on sexually active men from the same patient cohort. Of 511 study participants, 310 (60.7%) had ED and were sexually active. The IIEF orgasmic function domain (IIEF-OF; including IIEF questions 9 and 10) increased significantly with tadalafil versus placebo (p = 0.048), as did IIEF-Q9 (p = 0.045) but not IIEF-Q10 (p = 0.100). Compared with placebo, IIEF-OF, IIEF-Q9 and IIEF-Q10 decreased significantly with tamsulosin (all p < 0.05). These data reflect the ejaculation disorders associated with tamsulosin in a certain subgroup of patients. The IIEF intercourse satisfaction domain (IIEF-IS) and the IIEF-overall satisfaction domain (IIEF-OS) increased significantly with tadalafil (both p < 0.001). For tamsulosin, the change was not significant for IIEF-IS, while IIEF-OS decreased significantly (p = 0.009).

These are the only studies published so far showing that tadalafil improves LUTS to a similar extent as tamsulosin, an α-adrenergic antagonist that is widely prescribed for this condition. These are also the only studies showing a statistically significant increase in Qmax that is similar for both active treatments. Although these studies cannot give an answer comparing the two active treatments directly, tadalafil seems to be at least as efficient as tamsulosin while having an extra benefit in improving all aspects of sexual life.

Safety issues

All of these studies reported that tadalafil is not only efficacious but also a safe treatment. As in the classic ED trials, the most common side effects were headache, dyspepsia, nasal congestion, flushing and back pain. In the pooled analysis of data from four randomized, double-blind, placebo-controlled, 12-week, parallel-design, multinational LUTS/BPH studies, the incidence of headache, back pain and dyspepsia was 3.8%, 2.5%, 2.1% and 2.6%, 1.2%, 0.2% for the tadalafil 5 mg and placebo group, respectively. Treatment discontinuation rates due to adverse events were 2.7% and 1.2% for the tadalafil 5 mg and placebo group, respectively [Porst et al. 2013b]. Brock and colleagues [Brock et al. 2013] reported similar findings without any significant difference in adverse events between patients with or without ED. In the open-label extension study, no new or unexpected adverse event was recorded while treatment discontinuation due to adverse events was 5.2% without significant differences between placebo and all tadalafil doses used [Donatucci et al. 2011].

For several years, well before data became available, concerns were raised in terms of combining an α-adrenergic antagonist with a PDE5i. Giuliano and colleagues [Giuliano et al. 2006], in a randomized, double-blind, placebo-controlled, crossover study in 18 healthy middle-aged men who received alfuzosin 10 mg daily for 7 days and either a single 20 mg dose of tadalafil or placebo on day 7 reported that tadalafil 20 mg showed no clinically relevant hemodynamic interactions with alfuzosin 10 mg daily. Goldfischer and colleagues [Goldfischer et al. 2012], reported on the safety of daily coadministration of alpha-blockers with tadalafil 5 mg in men with BPH-associated LUTS. All patients were stable on α-adrenergic antagonists for 4 weeks as recommended by US Food and Drug Administration (FDA) and European Medicines Agency (EMA) precautions [Hatzimouratidis et al. 2010]. The proportion of patients who reported treatment-emergent dizziness (due to orthostatic hypotension) was not significantly different between the two treatment groups (tadalafil 7%; placebo 5.7%; p = 0.403). No difference between treatment groups was observed with respect to patients meeting the criteria for a positive orthostatic test (30 per treatment group, p = 1.00). However, consistent with the results of previous clinical pharmacology studies of healthy subjects, a trend was seen for increased hemodynamic signs and symptoms in men taking nonuroselective alpha-blockers, most notably those taking doxazosin.

Is there still a role for combination therapy?

Since the coadministration of tadalafil and α-adrenergic antagonists is safe when following the proper instructions, another question that arises is the possible role of combination treatment in patients with BPH-associated LUTS, especially using the new more uroselective α-adrenergic antagonists.

Animal and clinical data have provided preliminary evidence for the benefits of combining α-adrenergic antagonists and PDE5i [Giuliano, 2008; Oger et al. 2008]. Bechara and colleagues [Bechara et al. 2008] reported on the combination of tadalafil (20 mg/day) plus tamsulosin (0.4 mg/day) to tamsulosin alone in 20 men with LUTS. This was a randomized, double-blind, crossover design, 12-week study. Improvements of IPSS score and IPSS QoL were significant with both treatments but greater with the drug combination. Both regimens similarly improved the maximum flow rate and decreased the PVR from baseline (p < 0.001) with no significant differences between tamsulosin alone versus tamsulosin and tadalafil (p > 0.05). The IIEF improved with tamsulosin plus tadalafil (p < 0.001) but not with tamsulosin alone (p > 0.05). The General Assessment Question (GAQ) showed that all patients preferred the combination scheme. No serious adverse events were recorded while only two patients (one in each group) discontinued treatment due to an adverse event (headache and cutaneous rash, respectively). Regadas and colleagues [Regadas et al. 2013], compared the combination therapy of tamsulosin/tadalafil taken daily to tamsulosin/placebo. A total of 40 men with BPH-associated LUTS were randomized to tamsulosin 0.4 mg/tadalafil 5 mg or tamsulosin 0.4 mg/placebo once daily for 30 days. The primary end point was to demonstrate changes in urodynamic variables in the voiding phase, detrusor pressure at maximum flow (PdetQmax) and maximum flow rate (Qmax). PdetQmax showed a significant reduction in tamsulosin/tadalafil group (13 ± 17.0) compared with tamsulosin/placebo (−1.2 ± 14.35) group (p = 0.03). Qmax increased in both groups, tamsulosin/tadalafil (1.0 ± 2.4) and tamsulosin/placebo (1.4 ± 2.4), but the difference was not significant between treatment groups (p = 0.65).

Recently, data on the combination of tadalafil with finasteride (a 5α-reductase inhibitor) have been published [Casabe et al. 2014]. This study was an international, randomized, double-blind, parallel study including men with prostate volumes 30 ml or greater. The combination of tadalafil 5 mg and finasteride 5 mg improved IPSS significantly compared with finasteride monotherapy at all time points (4, 8 and 16 weeks; p ≤ 0.022). IPSS improved by 1.7, 1.4 and 1 more in the combination group compared with the finasteride-only group at the above time points, respectively. As expected, IIEF improved significantly in the combination group (p < 0.001). Combination therapy was well tolerated and most adverse events were mild/moderate. Interestingly, almost no sexual adverse event has been reported in the combination group.

While these preliminary data show that combination therapy may provide additional efficacy benefits, it is questionable whether these benefits are of clinical importance. In addition to significantly increasing the treatment cost, new data are required and combination therapy currently should be considered only in clinical trials.

Conclusions

ED and BPH-associated LUTS are epidemiologically linked and share common pathophysiological pathways. Tadalafil 5 mg once daily is approved for the treatment of LUTS in men with or without ED. Its efficacy is well established, its safety profile is well known and it can provide a treatment alternative to currently established treatments for LUTS. In addition to these facts, tadalafil is an established treatment for ED and is the only drug available today that can treat simultaneously two conditions that are highly prevalent in aging men. Moreover, sexual adverse events commonly associated with α-adrenergic antagonists or 5α-reductase inhibitors are avoided. While the efficacy of tadalafil is irrelevant to concomitant ED, men having both conditions seem to benefit the most from this new treatment.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The author is a lecturer and received honoraria from Eli Lilly.

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Treating BPH: What’s the Difference Between Cialis and Flomax?

Benign prostatic hyperplasia (BPH) is a condition that affects the prostate gland, which is part of a man’s reproductive system. BPH can cause uncomfortable urinary symptoms, like a frequent or urgent need to go. This can occur in the middle of the night sometimes.

BPH is common among older men. It affects up to 50 percent of men in their 50s and as many as 90 percent of men in their 80s.

Treatment for BPH has come a long way in the last two decades. Today, several medicines are available to relieve urinary symptoms. Tadalafil (Cialis) and tamsulosin (Flomax) are just two of the drugs prescribed for BPH. Here’s a deeper look at what BPH is, how these medicines work, and their possible side effects.

Normally, the prostate adds fluid to semen. As you age, the gland can start to grow, which may cause problems.

The urethra, which is the tube urine travels through on its way out of the bladder, runs right through the prostate. Over time, the prostate can grow large enough to press down on and squeeze the urethra. This pressure narrows the exit.

This can make it more difficult for the bladder to release urine. Eventually, the bladder may become so weak that it can’t release urine normally.

  • lifestyle changes, such as training the bladder to reduce bathroom trips or drinking fewer alcoholic and caffeinated beverages to reduce the urge to go
  • medicines that relax the muscles of the prostate and bladder
  • procedures to remove excess prostate tissue

Cialis was originally developed to treat erectile dysfunction (ED), which is difficulty getting an erection. Researchers then discovered that the drug also helps relieve BPH symptoms. In 2011, the U.S. Food and Drug Administration approved Cialis for men who have both BPH and ED.

In ED, Cialis works by increasing the levels of a chemical called cyclic guanosine monophosphate, or cGMP. This chemical increases blood flow to the penis. The chemical also relaxes muscle cells in the bladder and prostate. This may be why it eases the urinary symptoms of BPH.

Cialis was approved for BPH after studies had found men who took 5 milligrams per day had improvements in both BPH and ED symptoms.

Most side effects from Cialis are mild. These can include:

  • nausea
  • diarrhea
  • a headache
  • indigestion
  • back pain
  • muscle pain
  • a stuffy nose
  • flushing of the face

Because Cialis widens your arteries to let more blood flow to the penis, it can cause your blood pressure to drop. That’s why the drug isn’t recommended for men who already take drugs that lower blood pressure such as nitrates or alpha-blockers. Consuming alcohol can also increase this risk.

In rare cases, men have suddenly lost vision or hearing after taking Cialis and other drugs in its class. If you experience hearing or vision loss, you should tell your doctor right away.

Cialis is available in generic form, which can cost less than the brand name version.

Tamsulosin (Flomax) was one of the first drugs available to treat the urinary symptoms of BPH. It’s been around since the late 1990s.

Flomax is part of a drug class called alpha-blockers. These drugs work by relaxing smooth muscles in the prostate and bladder neck to let urine flow more freely.

Flomax, or another alpha-blocker, is usually the first drug prescribed for men with mild to moderate urinary symptoms from BPH.

Because Flomax also affects blood pressure, you shouldn’t use it if you already have low blood pressure. Since its effects on blood pressure are brief and somewhat unpredictable, it’s not a good choice to treat high blood pressure.

Side effects from Flomax are usually mild. These can include:

Rarely, men have developed more serious side effects, such as:

  • dizziness or lightheadedness when standing or sitting up, which can be due to low blood pressure
  • fainting
  • chest pain
  • prostate cancer
  • a heart attack
  • an allergic reaction

Talk to your doctor before taking Flomax if you’ve had a severe allergic reaction to sulfa drugs. You may be at an increased risk for an allergic reaction to Flomax.

This drug can also affect your eyes, and it may interfere with cataract or glaucoma surgery. If you’re planning to have eye surgery, you should tell your doctor before starting Flomax.

Talk to your doctor before taking Flomax if you also take an ED drug or blood pressure medication. When combined with Flomax, these can lower your blood pressure too much and increase symptoms like lightheadedness or fainting.

Like Cialis, Flomax is available in generic form, which can cost less than the brand name version.

Cialis and Flomax are just two of many drugs that are approved to treat BPH. Whenever you’re considering any new medicine, it’s important to discuss all of your options with your doctor. Find out how these drugs can help your symptoms and what side effects they might cause. Choose the drug that offers the best relief with the fewest risks.

Which drug you choose may also depend on what other health conditions you have. Cialis is a good option for men with both BPH and ED. Flomax is primarily for BPH. Both of these drugs can cause a drop in blood pressure and wouldn’t be a good choice for you if you already have low blood pressure or if your blood pressure varies.

Last medically reviewed on January 25, 2016

How Tadalafil Helps With Benign Prostatic Hyperplasia

Naveed Saleh, MD, MS, is a medical writer and editor covering new treatments and trending health news.

Verywell Health articles are reviewed by board-certified physicians and healthcare professionals. These medical reviewers confirm the content is thorough and accurate, reflecting the latest evidence-based research. Content is reviewed before publication and upon substantial updates. Learn more.

Jamin Brahmbhatt, MD, is board-certified in urology. He is an assistant professor at UCF College of Medicine and chief of surgery at Orlando Health South Lake Hospital.

Cialis (tadalafil), an erectile dysfunction medication, can also treat urinary symptoms of benign prostatic hyperplasia (BPH), or enlarged prostate.

Prior to this finding, there were only two options for urination difficulties in those with BPH:

  • Alpha blockerslike Flomax (tamsulosin) that relax tissue and muscles around prostate
  • 5-alpha reductase inhibitors like Proscar (finasteride) and Avodart (dutasteride) that shrink the size of the prostate over six to 12 months

Although alpha blockers and 5-alpha reductase inhibitors are effective for helping with urination, they can have side effects that affect sexual function. Alpha blockers can cause retrograde ejaculation, or when semen enters the bladder and the person may no longer see ejaculate come out anymore; and 5-alpha reductase inhibitors can decrease libido. Some individuals take both medications, which can really dampen their sexual functioning if they are having both side effects.

Since 2011, Cialis (tadalafil) has been approved by the FDA for daily use in treatment for men with enlarged prostate, or BPH. It’s the same medication as for sexual and erectile dysfunction, but it’s just taken daily as a lower dose. This has the potential to make Cialis doubly beneficial for both urination and sexual functioning in men with enlarged prostate.

What Is BPH?

If you have BPH, you probably need no introduction to its inconvenient, annoying and sometimes very serious symptoms. However, for all of us who are uninitiated, here’s some info on this condition.

Benign prostatic hyperplasia is a noncancerous (nonmalignant) enlargement of the prostate gland. In men, the prostate makes part of the male ejaculate, or semen. In men with BPH, the prostate can become significantly larger and cause urinary obstruction. Of note, the prostate is a doughnut-shaped gland that surrounds the urethra or “pee” tube; the prostate sits just below the bladder.

Although prostate cancer can include enlargement and tissue expansion and many of the same initial symptoms as BPH, BPH isn’t cancer. It’s a benign condition which most men aged 50 or older experience to some degree. Moreover, BPH likely confers no additional risk of developing prostate cancer.

In most men, BPH is asymptomatic and causes no recognizable symptoms. About one-third of American men, however, can experience the following initial symptoms:

  • Weak urine stream which starts and stops
  • Feeling that you still have to pee even after you just finished urinating
  • Trouble initiating a urine stream (hesitancy)
  • An increased urge to urinate at night (nocturia)

Over time, BPH can lead to more serious problems such as urinary tract infections, kidney, and bladder damage. (The obstruction caused by a hyperplastic prostate can cause urine backup which damages the kidney and bladder.)

Initial treatment for BPH is behavior changes, such as decreasing excess caffeine intake. Men with symptomatic BPH typically have the option to start alpha blockers (tamsulosin, terazosin or doxazosin) and 5-alpha reductase inhibitors (finasteride or dutasteride).

Although both types of BPH medications contain alpha in their names the mechanisms of these drugs are completely different. Alpha blockers relax smooth muscle in the bladder neck and prostate in order to improve urine flow and relieve urinary obstruction. While alpha blocker medication acts quickly within seven days typically, 5-alpha-reductase inhibitors target the hormonal underpinnings of BPH and not only help with urinary flow, but, if taken long enough, can actually shrink the prostate and postpone the need for surgery.

Peak effects with 5-alpha reductase inhibitors take longer to be noticed and are achieved after six months of use. The effects of these two types of medications have a greater effect when used together.

Beyond medication, urologists can offer surgical treatments like prostate resection (remove parts of the prostate), implants (lift and hold the prostate tissue so it no longer blocks the urethra), laser ablation (laser used to remove excess tissue), or steam vaporization (steam used to remove excess tissue). Even these surgeries can have sexual side effects.

Adding Cialis to the Mix

For reasons we can all probably appreciate, a big complaint among many men receiving treatment with alpha blockers, 5-alpha-reductase inhibitors or both is that in 5% to 15% of people, such meds mess with erectile function, libido, and ejaculation. To counteract this unwanted adverse effect, urologists and primary care physicians have started adding Cialis to the medication mix.

Furthermore, in 2011, the FDA had already approved Cialis for treatment of BPH symptoms, too. Thus, in men with BPH, Cialis demonstrates double efficacy—it helps with urination, and it helps with erectile dysfunction.

Fortunately, the science supports the practice of adding drugs chiefly aimed at erectile dysfunction to BPH medication regimens. In a huge randomized-control trial sponsored by Eli Lilly, makers of Cialis (go figure), 695 men were given either Cialis or placebo in addition to the 5-alpha reductase inhibitor finasteride.

Results were very encouraging with statistically significant improvements in sexual desire, orgasmic function, erectile function, and overall sexual satisfaction observed in those taking Cialis with finasteride. Moreover, adverse effects were few and tolerable. Results were measured at four, 12, and 26 weeks of therapy using a questionnaire titled the International Index of Erectile Function.

Closing Thoughts

If you or someone you love is experiencing sexual difficulties secondary to BPH medications like finasteride and aren’t already on Cialis, be sure to discuss it with your primary care physician or urologist. The addition of Cialis to your treatment regimen may help with your sex life and symptoms of BPH itself.

On a related note, because of its hormonal effects, lower-dose finasteride is also marketed as Propecia, a drug given for hair loss. Although people who typically take Propecia are younger men with fewer erectile dysfunction issues, and Propecia is lower dose than Proscar, Propecia may also interfere with sexual functioning and possibly male fertility. If you’re taking finasteride to prevent hair loss and are experiencing erectile dysfunction, libidinal problems, or fertility issues, be sure to inform your prescribing physician.

Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.

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By Naveed Saleh, MD, MS
Naveed Saleh, MD, MS, is a medical writer and editor covering new treatments and trending health news.

Cialis treatment for BPH

Benign prostatic hyperplasia is also known as BPH. It is currently one of the most common health conditions among older men.

The majority of us know it is all about having urinary problems. It is also the reason why the rectal examination might be imminent at some point in our lifetime.

However, there’s much more to know about this widespread condition. Modern medicine discovered that medications formerly used for erectile dysfunction might also work for BPH symptoms.

As you will see in this article, this is good news and an appropriate option for many patients with BPH.

So, is it possible to solve your erection problems and your urinary symptoms at the same time?

Let’s see what the medical evidence has to say. We will also review other options available to treat symptoms of BPH.

What is BPH?

The term benign prostatic hyperplasia (BPH) is commonly used to address benign enlargement of the prostate. Such a change in size typically causes a series of symptoms associated with the urinary tract.

However, if we dig a bit into terms, we will realize hyperplasia is a type of histological growth. Thus, the term BPH is a histological diagnosis. If we are not performing any biopsy, we can use the term “benign prostatic enlargement.” The latter describes the disease clinically. Not according to biopsy data, we have not yet confirmed (1).

Regardless of the term, we choose to use, BPH is caused by an adenoma (not the same as adenocarcinoma) of the prostate. It changes the configuration of the prostate and causes bladder outlet obstruction.

When it is severe, this obstruction may ultimately affect the bladder and the kidneys. The level of obstruction is variable.

It does not depend on the size of the prostate but the location of the adenoma or adenomata. Thus, we can find patients with a large and highly distorted prostate and no major symptoms. But another patient may have a smaller prostate and more concerning symptoms (2).

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Signs and Symptoms of BPH

As we mentioned above, symptoms of BPH are caused by bladder outlet obstruction and retention of urine. They do not depend on the size of the prostate as much as they rely on the site of the alteration.

For example, a small growth at the bladder neck may cause more severe symptoms than a larger growth in the lateral lobes of the prostate (3).

The most common signs and symptoms are also known as lower urinary tract symptoms or LUTS. They are further divided into storage, voiding, and post-micturition symptoms (4).

Storage symptoms of BPH include:

Voiding symptoms of BPH include:

Post-micturition symptoms of BPH include:

    • A sensation of incomplete emptying of the bladder

Since BPH is a slow-progressing condition, patients get used to them, may not have complaints, and become asymptomatic. However, these patients may have an acute case of urinary retention. They may even have blood in the urine, renal failure, and other complications.

Thus, we can say that BPH causes a varying degree of obstruction of the urinary tract. According to each case, patients may or may not display significant symptoms (5).

How Cialis works for BPH

It is not rare to find cases of benign prostatic hyperplasia and erectile dysfunction in the same patient. It is a prevalent association. Not because BPH causes erectile dysfunction.

The exact cause of their association is not known. However, they are both conditions that become more prevalent in aging men (6).

Cialis, also known as tadalafil, is a drug typically used to treat erectile dysfunction. It works with an enzyme called phosphodiesterase (PDE). This enzyme contributes to the signalization inside the cell.

It works with molecules called cAMP and cGMP. Tadalafil (Cialis) inhibits a subtype of phosphodiesterase called PDE5, which interacts with cGMP.

This enzyme can be found in the smooth muscle of the corpus cavernosum of the penis and the blood vessels. It is also found in visceral smooth muscle, including the prostate, the urethra, and the bladder (7).

In simple words, what Cialis does is causing relaxation of the smooth muscle. However, it is important to note that while Cialis alleviates symptoms, it in no way shrinks the prostate.

Cialis enters the organism, inhibits PDE5, and both nitric oxide and cGMP levels go up. As a result, the patient will achieve better erections and improve their LUTS at the same time (7, 8).

Is it an effective treatment?

It sounds very good in theory. But is Cialis effective in the medical practice to improve the symptoms of patients with BHP?

They do, according to four different randomized, double-blind, placebo-controlled trials (9, 10, 11, 12). These studies used tadalafil only once a day in men with LUTS diagnosed BPH. Additionally, one of these trials was performed in men with existing BPH and erectile dysfunction.

The clinical trials showed that using tadalafil once a day results in significant improvements in BPH symptoms in men.

The clinical trial lasted 12 weeks, and patients under 5 mg pills of Cialis had improved their quality of life compared to placebo patients. It was also noted that the improvements did not go any further by using a higher dose.

BPH symptoms started to improve after the first week of treatment in one trial (10). In another, it took 2 weeks of treatment to start seeing a significant difference (12). This improvement was maintained after one year of medical follow-ups.

Side effects

According to the clinical evidence, tadalafil may have the following side effects. In order of frequency, they are as follows:

The majority of these adverse reactions were found in a small proportion of patients (1-2%). 90% of them were reported to be of mild or moderate intensity.

4% of patients discontinued the treatment of tadalafil due to the presence of adverse events. This discontinuation rate was reduced to 2.9% in patients who had both lower urinary tract symptoms and erectile dysfunction (13).

There were no relevant changes in PSA levels, no events of urinary retention, and no increases in the post-void residual volume (13).

Natural alternatives for BPH

There’s still another alternative in natural solutions with no adverse effects. They are herbal medicines and natural remedies that will soothe your symptoms.

We can list the following as an example:

Boron

    • : There is much evidence about boron as a suitable alternative to improve prostate health. It has been found to reduce the incidence of prostate cancer, too. This is a trace mineral, and we only need small amounts. But covering our daily requirements may significantly improve PSA levels naturally. It will also reduce in half the risk of cancer. This trace mineral can be found in foods but in a very small proportion. Thus, it is recommended to find a supplement that makes a real difference. It is a form of dietary prevention of BPH progression to prostate cancer (14).

Conclusion

Benign prostate hypertrophy is a common problem as we age. It is typically associated with additional health problems, especially in men’s erectile function.

Sexual problems may also be a side effect of certain medicines and medical procedures to treat BPH and prostate cancer. That includes tamsulosin (Flomax) and other pills. So, patients may feel inclined to neglect their symptoms to avoid side effects.

Recent studies have shown that Cialis, a medication formerly used for cases of erectile dysfunction, may also improve urinary symptoms in BPH.

It does so by relaxing the smooth muscle of the urinary tract and improving the blood flow.

However, it is important to bear in mind that while it helps to relieve symptoms, it does not treat the root of the problem and can have side effects.

Among natural treatments for this condition, we can count minerals such as zinc and boron. There are also flavonoids found in berries and stinging nettle.

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