PDE5-Is for the Treatment of Concomitant ED and LUTS/BPH

Epidemiologic data in adult men exhibit a strong relationship between erectile dysfunction (ED) and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH), indicating that men affected by ED should also be investigated for LUTS/BPH and those presenting with storage or voiding LUTS should be investigated for co-morbid ED. Common pathophysiolgical mechanisms underlying both LUTS/BPH and ED, including alteration of NO/cGMP or RhoA/Rho-kinase signaling and/or vascular or neurogenic dysfunction, are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Several randomized controlled trials and only a few reviews including all commercially available PDE5-Is demonstrated the safety and efficacy of these drugs in the improvement of erectile function and urinary symptoms, in patients affected either by ED, LUTS, or both conditions.


Introduction
Erectile dysfunction (ED) and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) are common conditions in middle-aged or older men. Several reports indicated that patients with ED have a higher prevalence of LUTS strictly related to the urinary symptoms severity [1••]. Although the underlying mechanisms for the relationship between ED and LUTS/BPH men are not fully understood, it has been hypothesized that impaired NO/cGMP signaling could be the relevant underlying determinant for the pathophysiology of both ED and LUTS/BPH, suggesting that phosphodiesterase type 5 (PDE5) inhibitors (Is) are beneficial for the treatment of both conditions [2, 3••, 4-6].
PDE5 gene and protein expression has been described across the whole human lower urogenital tract, with different patterns of appearance [5, 7•]. The mechanism of action of PDE5-Is on LUTS/BPH includes several potential sites of actions such as the prostate and/or bladder [8,9]. The remarkable improvement of urodynamic parameters during treatment with PDE5-Is, both in men with spinal cord injury [10] or during continence recovery after radical prostatectomy for prostate cancer [11], underline the importance of the bladder as a target of PDE5-Is in LUTS. In addition, pelvic ischemia due to the pelvic artery insufficiency, caused by metabolic syndrome (MetS), can induce functional and morphological changes of the bladder and prostate, that can be restored by the use of PDE5-Is [12,13].
At the present time, several clinical trials on the use of PDE5-Is -either alone or in combination with other drugs (such as α-blockers) in men with LUTS/BPH and comorbid ED -have been reported in literature [3••]. All commercially available PDE5-Is have been tested in men with LUTS/BPH, with or without ED, by analyzing both urinary and sexual symptoms.
The aim of the present review is to summarize the current literature concerning the use of PDE5-Is for the treatment of LUTS/BPH and concomitant ED by analyzing epidemiological data, common pathophysiological pathways and efficacy as well as safety outcomes of clinical trials on PDE5-Is for ED and LUTS/BPH.

Epidemiology Data Concerning Comorbidity of ED and LUTS/BPH
Several national or cross-national studies, based on an unselected population of LUTS/BPH or ED patients, demonstrated a tight correlation between LUTS/BPH and ED. We analyzed the results of the most important single center and cross sectional trials.
The Cologne Male Survey, a community-based study in 4477 men aged 30-80 years, demonstrated that the overall prevalence of LUTS was significantly higher in men with ED than in those without ED (72 % vs. 38 %) [15]. Similarly, in another study from UK enrolling 11,327 men, with median age of 60 years at the diagnosis of ED, with any recorded LUTS/ED, the odds ratios (OR) for ED in men with LUTS compared to those without LUTS were: storage LUTS 3.0, voiding LUTS 2.6 and both storage and voiding LUTS 4.0. Moreover, LUTS diagnosis preceded ED in 63.1 % of patients by a mean of 4.8 years [17].
More recently, several authors have looked for the correlation between LUTS and ED in a population screened for prostate cancer. In particular, in a Brazilian study on 1008 consecutive patients enrolled in a prostate cancer screening program, with a mean age of 61.2 years (range 45-87), only 5.4 % of the patients without ED had severe LUTS, compared to 27.1 % of patients with severe ED (P<0.001) [19].

Multicenter Trials
Several cross-sectional multicenter trials investigating the epidemiological association between LUTS and ED have been published in the last 10 years (see Table 1).
The National Health and Social Life Survey, a community-based involving 1410 men aged 18-59 years demographically representative of US adults, demonstrated that LUTS are significant risk factors for ED, with an OR of 3.13 [14].
Later on in 2003, three different cross-national studies were published. In a study carried out in Brazil, Italy, Japan and Malaysia on 2412 men aged 40-70 years, Nicolosi et al. [20] evaluated the prevalence of ED and associated factors among men without concomitant diseases. Among 1335 healthy men, the prevalence of ED was 16.1 %. In this population, age, cigarettes smoking and LUTS were all associated with an increased risk of ED. The UrEpik study group, including 4800 men aged 40-79 years, from Auxerre, Birmingham, Boxmeer and Seoul [21], demonstrated that both the presence of BPH and LUTS severity were associated with an increased risk of ED, similar to that observed in subjects with diabetes and hypertension. In addition, the results of the Multinational Survey of the Aging Male (MSAM-7), a survey in 12,815 men aged 50-80 years conducted in the United States and six European countries to investigate the relationship between LUTS and ED in older men, clearly demonstrated that erection problems significantly increased with both age and LUTS severity [22]. In this study, ED was reported by 30 %, 51 %, and 76 % of study participants aged 50-59 years, 60-69 years, and 70-80 years, respectively (p<0.001) and in 43 %, 66 %, and 83 % of men with mild, moderate, and severe LUTS, respectively (p<0.001).
The Tampere Aging Male Urological Study, a prospective population-based postal survey in Finland in 1683 men aged 50-70 years followed for 5 years, reported an association between the severity of ED at baseline and the incidence of LUTS or bother during follow-up [16]. In line with these data, the European Male Aging Study, a multicenter population-based survey, performed on more than 3400 subjects across eight European centers, found that LUTS severity was significantly associated with ED and lower quality of life independent of other associated morbidities [27]. In 2008, McVary et al. published the retrospective US claims data analysis of 81,659 men with a mean age of 57 years. The authors analyzed men with a new diagnosis or medication for ED, and showed a baseline LUTS/BPH prevalence of 1.5 %, and demonstrated a total prevalence of 7.6 % after two years follow-up [18].
Evidence linking disorders of the prostate and bladder with LUTS and ED is irrefutable, but the contribution of metabolic, cardiovascular, and endocrine factors cannot be discounted. In 2010, the Men in Australia Telephone Survey (MATeS) study, including 5990 men aged ≥40 years, evaluated lifestyle and biomedical associations as possible causes of ED, prostate disease, LUTS and perceived symptoms of androgen deficiency in a representative population of middle-aged and older men. They demonstrated that diabetes mellitus and cardiovascular diseases were both DAN-PSS = Danish Prostate Symptom Score; IPSS = International Prostate Symptom Score; ED = erectile dysfunction; LUTS = lower urinary tract symptoms; BPH = benign prostatic hyperplasia; SF = sexual function; QoL = quality of life; ICS = International Continence Society; KEED = Cologne Erectile Inventory; IIEF = International Index of Erectile Function associated with ED, and hypertension was strongly associated with LUTS and perceived symptoms of androgen deficiency, while cigarettes smoking and depressive symptoms were the only variables independently associated with prostate diseases [23]. This was a first clue of the potential relationship between metabolic syndrome (including BMI and waist circumference), LUTS and ED.

Pathophysiology and Mechanisms of Action of PDE5-Is on both ED and LUTS
There is an increasing body of evidence that all theories currently proposed for a common causality for both ED and LUTS are interconnected and that treatment options may overlap allowing prevention and/or treatment of both conditions simultaneously. These pathophysiolgoical pathways, which are also possible targets for the treatment of both ED and LUTS/BPH with PDE5-Is, are: a) modification of the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway; b) improvement of the RhoA/Rho-kinase (ROCK) pathway; c) hyperactivity of autonomic nervous system; d) atherosclerosis of pelvic vessels (see Fig. 1).
The NO/cGMP pathway in the regulation of erection has been well clarified [28]; currently, there is a body of evidence for a role of NO in the regulation of smooth muscle tone of bladder, prostate and urethra [29]. In particular, calciumdependent NOS, including endothelial (eNOS) and neuronal (nNOS) have been described in several lower urinary tract (LUT) tissues. The nNOS isoform was identified in nerve terminals of the prostate, specifically in the peripheral and transitional zones [30]. NOS activity has also been described in the urothelium, smooth muscles, blood vessels, and nerves of the bladder [31]. A potential role for the NO pathway in LUTS/BPH is suggested by the proof of antiproliferative and pro-apoptotic effects of NO donors on culture of bladder, prostate and urethra smooth muscle cells [32].
An overactivity of the contractile RhoA/ROCK pathway has further been indicated as a common pathological mechanism underlying both ED and LUTS. Pathological conditions that alter relaxant/contractile mechanisms balance, such as those associated with reduced function of NO production and/or overactivity of RhoA/ROCK contractile signaling (i.e., aging, hypertension, smoking, diabetes and MetS), cause impaired smooth muscle relaxation in both penile and LUT tissue function, leading to ED and uncontrolled detrusor contractility [8,33,34]. Up-regulated RhoA/ROCK signaling has been demonstrated in corpora cavernosa [35] and bladder [36] of spontaneously hypertensive rats (SHR), a rat strain predisposed to erectile dysfunction, BPH and overactive bladder. Similarly, hyperactivation of RhoA/ROCK signaling has been demonstrated in penis and bladder tissue in an animal model of MetS [37,38]. The inhibition of ROCK can limit bladder hyperactivity, reduce contractions in bladder strips from SHR and improves erection [35]. Interestingly, PDE5 inhibition with vardenafil reversed RhoA/ROCK hyperactivation in SHR; thus, preventing deterioration of urodynamic parameters [9]. Another important mechanism linking ED to LUTS is the autonomic hyperactivity with an increased sympathetic tone [39]. Various subtypes of α 1 -adrenergic receptors have been identified in the bladder, prostate and penile tissue, mediating the tone of smooth muscle vasculature [40,41]. In particular, α 1A -and α 1D -receptors have been recognized as the predominant α-adrenoceptor subtypes in the penis. α 1A -adrenoceptors identified in bladder neck and prostate are involved in voiding symptoms while α 1D -adrenoceptors, concentrated in hypertrophied detrusor muscle, are involved in storage symptoms [42]. Correlation between autonomic hyperactivity and LUTS/ED has been further suggested by preclinical studies using SHRs, which were shown to develop increased autonomic activity, BPH, LUTS, and ED [43,44].
Atherosclerosis of the penis and lower urinary tract is indicated as a further potential mechanism which ties all the previously described pathways, since pelvic atherosclerosis reduces NO signaling, up-regulates RhoA-ROCK, and is a component of the metabolic syndrome/autonomic hyperactivity. Traditional risks factors for ED and atherosclerosis, such as diabetes mellitus and hypertension, can also affect LUTS/BPH [45,46]. Several pre-clinical and clinical trials have demonstrated that bladder ischemia/hypoxia can be strongly associated with alteration of erectile and LUT tissues [47,48]. A positive immunostaining for the hypoxiainducible factor 1α (HIF-1α), a protein not present in normal cells but induced under hypoxic conditions, has been Fig. 1 Schematic presentation of common pathophysiological mechanisms linking erectile dysfunction (ED) to lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). All components are potential targets for phosphodiesterase type 5 inhibitors (PDE5-Is). NO nitric oxide; cGMP cyclic guanosine monophosphate; ROCK Rho-kinase; BPH benign prostatic hyperplasia; LUTS lower urinary tract symptoms; ED erectile dysfunction; PDE5-Is phosphodiesterase type 5 inhibitors identified in prostatic tissue from patients with BPH, while no HIF-1α immunostaining was detected in tissue from healthy controls [49]. Finasteride, a 5α-reductase inhibitor, reduces prostate size through reducing HIF-1α and other hypoxiarelated growth factors, which can contribute to the growth of prostate [50]. In animal models of chronic ischemia of the lower urinary tract [12] and penis [51][52][53][54], administration of PDE5-Is restored normal oxygenation, thereby preventing tissue fibrosis and functional modifications.

Evidence Syntesis on PDE5-Is and LUTS/BPH
Tuncel et al. [72] screened 60 men with LUTS/BPH who were randomized to receive sildenafil only (n = 20), tamsulosin only (n=20) or the combination of sildenafil and tamsulosin (n=20) for 8 weeks. Sildenafil monotherapy was compared with combination treatment regarding erectile function and, in particular, the improvements of ques-

Tadalafil
Tadalafil has been more extensively and systematically investigated for the use in LUTS/BPH than any other PDE5-I. All tadalafil trials were randomized, double-blind, placebocontrolled trials in men with LUTS/BPH >6 months, aged ≥45 years, IPSS ≥13 at start of placebo lead-in period, and Q max between 4 and 15 ml/s. All trial participants had a 4-week washout and a 4-week placebo lead-in phase. Trial duration was usually 12 weeks and only the open-label trial lasted 52 weeks. Common efficacy parameters in all trials were IPSS (including IPSS storage and voiding sub-scores), BII, and IIEF in sexually active men with ED, with special focus on the erectile function (EF) domain of the questionnaire. Safety parameters included treatment-emergent adverse events (TEAEs), post-void residual urine, and Q max .
In 2007, McVary et al. [67] investigated 281 men randomly allocated to 5 mg tadalafil once daily for 6 weeks, followed by dose escalation to 20 mg once daily for another 6 weeks, or placebo for 12 weeks. The improvement of sexual function was significant for tadalafil vs. placebo (IIEF: +8.4 vs. +1.6, p<0.001). Moreover, LUTS improvement was greater with tadalafil vs. placebo at week 6 (mean improvement of IPSS: 49.3 % vs. 36.4 %, p=0.03) and week 12 (60.9 % vs. 42.7 %, p<0.01), while Q max was not significantly changed in both treatment groups throughout the study.
Roehrborn et al. [73] evaluated 1058 men with LUTS/BPH with or without ED. Patients were randomly allocated to receive tadalafil 2.5 mg, 5 mg, 10 mg, 20 mg or placebo once daily for 12 weeks. IIEF-EF significantly improved after 12 weeks of treatment: +5.59 for tadalafil 2.5 mg, +6.97 for tadalafil 5 mg, +7.98 for tadalafil 10 mg, and +8.34 for tadalafil 20 mg; the differences compared to placebo (+2.2) were significant for all tadalafil doses (p<0.001). Regarding LUTS, mean changes of IPSS from baseline to study end were also significantly different for all tadalafil doses: -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) as compared to placebo (−2.3) while Q max , although increased with increasing tadalafil dose, was insignificant for all treatment groups.
In a second study of Porst et al. [75], the authors randomized 325 men who were treated with either tadalafil 5 mg (n=161) or placebo (n=164). IIEF-EF score in sexually active men with ED improved after 12 weeks of tadalafil vs. placebo (6.7 vs. 2.0; p<0.001). Tadalafil also significantly improved IPSS from baseline to endpoint as compared to placebo (−5.6 vs. -3.6; p = 0.004), while uroflowmetry parameters did not significantly change at study end.
Recently, Oelke et al. [76] designed a randomized, double-blind, placebo-controlled, parallel-group study in men with LUTS/BPH. In total, 511 patients were randomized to placebo (n=172), tadalafil 5 mg (n=171), or tamsulosin 0.4 mg (n=168) once daily and were treated for 12 weeks. However, the study was not powered to directly compare both active compounds. Compared to placebo, sexual function significantly improved with tadalafil but not with tamsulosin in sexually active men with ED (IIEF-EF score +4.0, p<0.001 and −0.4, p=0.699, respectively). Moreover, LUTS/BPH significantly decreased with tadalafil and tamsulosin as compared to placebo as early as one week after start of treatment. Significant LUTS/BPH improvement was documented throughout the study period; at study end, IPSS decreased by −2.1 with tadalafil 5 mg (p=0.001) and −1.5 with tamsulosin 0.4 mg (p=0.023) relative to placebo. Finally, Oelke et al. first reported about a significant increase of Q max with both tadalafil and tamsulosin, as compared to placebo: Q max +2.4 ml/s for tadalafil (p = 0.009) and +2.2 ml/s for tamsulosin (p=0.014). This data was corroborated by similar improvements of average urinary flow rate with both tadalafil (+1.6 ml/s, p=0.002) and tamsulosin (+1.3 ml/s, p=0.023).
Donatucci et al. conducted a 1-year, open-label extension study reporting the long-term safety and maintenance of efficacy for the once daily use of tadalafil 5 mg in men with LUTS/BPH. The study population consisted of 427 men who completed the 12-week, double-blind, placebocontrolled period [73]. In total, 299 patients (69.9 %) completed the 1-year, open-label extension period. TEAEs were reported by 57.6 % of patients, with most TEAEs being mild (44 %) or moderate (45 %) in severity; the most common TEAEs (≥2 %) were dyspepsia, gastrooesophageal reflux disease, back pain, headache, sinusitis, hypertension and cough. Twenty-two patients (5.2 %) discontinued the study as a result of TEAEs. Changes in IPSS, IPSS irritative and obstructive sub-scores, IPSS health-related quality of life, BII, and IIEF-EF domain in sexually-active patients with ED were maintained after one year [77].
Regarding combination therapy of tadalafil and α-blockers, two trials were analyzed. Bechara et al. [78] randomized 30 men aged >50 years with LUTS/BPH into two groups to receive once daily tamsulosin vs. tamsulosin plus tadalafil 20 mg for 45 days and then switched to the other treatment mode for another 45 days. IIEF-EF significantly improved with tamsulosin plus tadalafil (p<0.001) but not with tamsulosin alone. Improvements of IPSS were statistically significant with both treatments but greater with combination therapy. Both regimens similarly improved Q max (p< 0.001) with no significant differences between tamsulosin monotherapy vs. combination treatment (p>0.05). In the other study, Liguori et al. [79] randomized 66 men with LUTS/BPH and co-morbid ED and allocated these patients into three treatment arms: alfuzosin 10 mg once daily (22 men), tadalafil 20 mg every second day (21 men), or a combination of both drugs (23 men). ED, as measured by the IIEF-EF domain score, improved with alfuzosin alone (+15 %) but much more with tadalafil alone (+36.3 %) or combination therapy (+37.6 %). LUTS/BPH, as measured by IPSS, significantly improved with alfuzosin (27.2 %) and combination therapy (41.6 %), but not with tadalafil alone (8.4 %). Increase in Q max was more pronounced with combination therapy (29.6 %) than with alfuzosin (21.7 %) or tadalafil monotherapy (9.5 %).

Vardenafil
Stief et al. [80] published the first randomized, doubleblind, placebo-controlled study with vardenafil. In this 8-week multicenter trial, the authors included 221 men who were equally distributed to vardenafil 10 mg (n=108) or placebo (n=113) twice daily. Sexual function was significantly improved by vardenafil as compared to placebo (IIEF-EF +7.5 vs. +1.5; p=0.0001). At the same time, there was a significant improvement of LUTS/BPH with vardenafil vs. placebo (IPSS −5.9 vs. -3.6; p =0.0013). Although Q max was more improved with vardenafil, the difference compared to placebo was not statistically significant (+1.6 ml/s vs. +1.0 ml/s; p=0.5614). The Jadad score assesses the quality of published clinical trials based methods relevant to random assignment, double blinding, and the flow of patients. There are seven items in total; the last two attract a negative score, which means that the range of possible scores is 0 (bad) to 5 (good). LL = lower limit; UL = upper limit Gacci et al. [81] compared the safety and efficacy of once-daily tamsulosin plus placebo vs. tamsulosin plus vardenafil 10 mg in 60 patients with LUTS/BPH in a randomized, double blind trial with a 12-week follow-up. Erectile function and LUTS were significantly improved with combination therapy as compared to tamsulosin alone (IIEF-EF combination +2.61 vs. tamsulosin alone +0.06, p=0.030; IPSS combination −3.11 vs. -1.67, p=0.039). Furthermore, vardenafil plus tamsulosin achieved an additional improvement of Q max compared to tamsulosin alone (+2.56 vs. + 0.07, p=0.034) Table 2.

Conclusions
Epidemiological data underlines the strong association between ED and LUTS, either in the general population or in urological patients. Moreover, ED and LUTS share several common pathways which can be a potential target for PDE5-Is, including NO/cGMP and RhoA/Rho-kinase pathways such as pelvic atherosclerosis and autonomic hyperactivity.
PDE5-Is are well tolerated and effective for the treatment of both ED and LUTS/BPH. Flushing, gastro-esophageal reflux, headache and dyspepsia are the most frequently reported adverse events. PDE5-Is significantly improve erectile function, as measured with the IIEF-questionnaire, and LUTS/BPH, as measured with the IPSS questionnaire, with an overall improvement of quality of life.
PDE5-Is can be considered as the first choice of treatment in men with both ED and LUTS/BPH but treatment of either ED or LUTS/BPH with PDE5-Is is also feasible. Nevertheless, further studies are needed to evaluate the long-term safety, efficacy, influence on disease progression, and costeffectiveness of PDE5-Is.