Treatment of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction

Abstract

This article summarizes years of challenging research on erectile dysfunction (ED), a condition that has an important social and cultural relevance. Preclinical and clinical research progress has led to new therapeutic approaches to ED in patients with different comorbidities and particularly in those with low urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). These goals were possible only by combined work of specialists and researchers of different and intertwined medical disciplines. Currently, tadalafil (5 mg/d) is the best choice; other phosphodiesterase-5 inhibitors (PDE5i) are not included among options, despite the growing evidence of therapeutic effects. Different regimens of tadalafil may be prescribed based on patient needs, severity of LUTS/BPH – ED profile, and clinical experience. An integrated approach is necessary to choose for a combined therapy with PDE5i and α-blockers following urological and cardiac counseling in terms of outcomes and adverse effects.

Keywords:

• Erectile dysfunction
• prostatic hyperplasia
• LUTS
• treatment

Introduction

Erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) share similar pathogenetic mechanisms [1]. Metabolic syndrome has been found to play an important role in BPH and ED etiology [1]. Also, patients with BPH may display low testosterone levels [2,3] and benefit from testosterone replacement therapy [4–6], as well as patients with ED. Chronic inflammation, vascular dysfunction, dyslipidemia and hormonal impairment occur in BPH [7–15]. Furthermore, urethral pain has been identified as an independent risk factor for ED development [16]. Different questionnaires and biochemical markers are used for the diagnosis and follow-up of these two conditions [17,18]. Currently, a number of surgical interventions can be performed in patients with BPH [19–24]. Despite surgery, the occurring of similar pathogenetic mechanisms in patients with ED and low urinary tract symptoms (LUTS)/BPH give rise to explore the possible medical therapeutic choices in such patients, whit respect to those drugs used for ED which positively impact on LUTS/BPH and those affecting the erectile function prescribed in patients with BPH. A review of such drugs follows.

Phosphodiesterase type 5 inhibitors (PDE5)

PDE5 is mainly found in the corpora cavernosa, the vascular and visceral smooth muscles, and platelets. PDE5i exhibit its inhibitory effect by binding competitively to the catalytic site of PDE5, thereby promoting cyclic guanosine monophosphate (cGMP) accumulation in the smooth muscle cells of corpora cavernosa. Therapeutic and adverse effects of PDE5i depend on their selectivity for PDE5 over other PDE isoforms, on their pharmacokinetic profiles and on the distribution of different PDE isoenzymes in the corpus cavernosum or penile vessels. Because different PDE isoenzymes are distributed over various tissues and a high concentration of PDE5 is present in the smooth muscle of the corpus cavernosum, the high selectivity for PDE5 over the other PDE isoenzymes is important for the increased therapeutic window of PDE5i. In addition to the selectivity for PDE5 over the other PDE isoenzymes, degree of PDE5 inhibition in tissues other than the corpus cavernosum plays a critical role in determining the tolerability of PDE5i.

Tadalafil

Tadalafil is a PDE5i suggested for moderate to severe LUTS/BPH with or without ED. Tadalafil at the dose of 5 mg once daily was approved in October 2011 in Europe and is the only PDE5I approved for LUTS/BPH with or without ED. PDE5 activity has been identified in the LUT, specifically in the prostate, urethra, and bladder. The smooth muscle areas of PDE5i interest in LUTS/BPH include the detrusor, prostatic stromal (prostate), vascular (artery), and urethral areas. All these areas have shown PDE5 activity and are potential target of PDE5i action. Prostate smooth muscle relaxation, detrusor muscle overactivity, and contraction of prostate tissue can be inhibited through cGMP increase achieved by either nitric oxide (NO) donors or PDE5Is. Additionally, PDE5i (including tadalafil, sildenafil, or the NO donor sodium nitroprusside) have been shown to attenuate α-adrenergic-induced contraction of isolated human prostate tissue. Thus, cGMP may contribute to the regulation of prostatic smooth muscle cell contraction. Improvements in both storage and voiding urinary symptoms observed with tadalafil may be due to smooth muscle cell relaxation and regulation in the bladder neck, prostate, and urethra with potential resulting modulation of the afferent nerve activity [25]. The relaxation of smooth muscle cells may increase blood flow through the supporting LUT vasculature system. PDE5 inhibition may then have an impact on LUTS/BPH through increased perfusion of the low urinary tract (LUT) resulting in increased oxygenation. Animal models suggest that the reduced symptoms may also be due in part to an enhancement of NO inhibition of the overactive afferent nerve activity within the LUT. Long-term efficacy may be due to continued smooth muscle cell relaxation of the LUT tissues with increased blood perfusion and oxygenation of LUT tissues due to improved function of the supporting vasculature and resulting modulation of the afferent nerve activity [25].

Efficacy of action of PDE5I monotherapy inED-LUTS/BPH

Several clinical studies have been conducted to assess the efficacy of PDE5i administration in patients with concurrent ED and LUTS. The main indexes used for this purpose are the International Prostatic Symptoms Score (IPSS), BPH Impact Index (BPH-II), International Index of Erectile Function (IIEF) scores and the maximum flow rate (Q_max) value. This section covers some of the most recent results in literature, and further studies will more clearly address the therapeutic effects of PDE5i. Gacci et al. [26] performed a meta-analysis of the studies comparing PDE5i administration versus placebo, combined therapy with PDE5i and α-adrenergic antagonists and monotherapy with α-adrenergic antagonists, showing a significant improvement of IPSS and IIEF scores compared with placebo. These results were confirmed by a meta-analysis, presenting the results of tadalafil monotherapy versus placebo in patients with isolated LUTS and concomitant ED. A significant total IPSS score decrease (−2.19 points) compared with placebo was observed, in addition to a statistically significant improvement of IPSS irritative and obstructive domains, BPH Impact Index and Quality of Life (QoL) parameter [27]. While the meta-analysis by Gacci et al. [26] showed no significant improvement of Q_max, Dong et al. [27] described a statistically significant change of this parameter in patients receiving tadalafil (5 mg/daily). In this meta-analysis, different patient enrollment criteria for tadalafil administration (patients with concurrent LUTS/BPH and ED and sexually active patients) were used. Such different enrollment criteria may explain the different results obtained for Q_max. Another randomized study showed a poor effect either on the urodynamic parameters of the urinary bladder contractility or in residual urine during long-term treatment with tadalafil [28]. This result aligns with that of Porst et al., which showed the absence of PSA level influence on the effect of the treatment with PDE5i [29]. In addition, baseline patient characteristics could also have influenced the result of the treatment with PDE5i in many studies. Gacci et al. [26] showed, by regression analysis, that patient age, baseline BMI, and baseline IPSS score significantly influenced the treatment effect. Younger age, low BMI, and higher baseline IPSS score led to a better effect of the treatment with PDE5i. Therefore, the ideal patient for treatment with PDE5i is a young man with high IPSS scores. These results enlighten the recent physiopathological mechanisms supposed to explain LUTS improvement during PDE5i administration, apart from mechanic changes. Indeed, PDE5i could influence LUTS by increasing vascularization and reducing ischemia because of nitrogen oxide interaction with cGMP, as well as a decrease in inflammatory and proliferative changes due to RhoA/RhoA-kinase activity.

Summarizing the results of all these studies, tadalafil (5 mg/daily) as monotherapy is justified in patients with BPH-LUTS with or without concurrent ED. The best candidate to this treatment is a young man with high IPSS score. Therapy does not usually change Q_max, residual urine, or serum PSA level. Any treatments for BPH can modify sexual function, but tadalafil can improve co-existing LUTS/BPH and ED [30,31].

Combined therapy with α-adrenergic antagonists and PDE5i

Administration of α-adrenergic antagonists is the first-line drug therapy in patients with BPH-LUTS. Different studies have shown the efficacy of combined therapy α-adrenergic antagonists and PDE5I. However, administration of this combination must be taken cautiously, because of the potential interaction effects leading to decreased blood pressure. This aspect has been evaluated in several studies. Kloner and colleagues studied the safety of tadalafil combined with two different α-adrenergic antagonists in a double-blind, placebo-controlled, randomized crossover study. The authors investigated hemodynamic effects during administration of doxazosin 8 mg for 7 d followed by the addition of tadalafil 20 mg and during the administration of tamsulosin 0.4 mg for 7 d followed by the addition of tadalafil 10 and 20 mg. In the first part of the study, patients receiving concomitant doxazosin and tadalafil reported a significant decrease of the mean maximum systolic blood pressure compared to placebo. In addition, three patients had significant dizziness not correlated with blood pressure values. In the second part of the study (tamsulosin administration in combination with tadalafil), no significant blood pressure lowering was reported after the addition of tadalafil [32]. Giuliano et al. [33] did not show significant hemodynamic changes in patients receiving the combination of tadalafil 20 mg and alfuzosin 10 mg daily. Singh et al. studied the efficacy of combined therapy with tamsulosin 0.4 mg/day and tadalafil 10 mg/d versus monotherapy with each drug. This randomized study included 133 patients with BPH-LUTS. The efficacy of combined therapy (IPSS score) appeared to be higher when compared with monotherapy with tadalafil (p < .05), but not monotherapy with tamsulosin. Moreover, the efficacy of combined therapy with regard to the ED symptoms (IIEF scale) was higher than in the tamsulosin group [34]. Liguori et al. evaluated the efficacy of alfuzosin and tadalafil in a cohort of 66 men with LUTS and ED, investigating changes in IIEF-5, IPSS, Q_max and average flow rate (Q_ave). IIEF-5 tended to improve with alfuzosin alone, and clearly improved with tadalafil alone, with greater enhancement experienced by combination therapy; the same effect was obtained for Q_max. IPSS improved with alfuzosin alone and in combination therapy, and a small, not significant increase, in tadalafil only group [35].

These studies have shown the efficacy of combined therapy with PDE5i and α-adrenergic antagonists in patients with LUTS. From these results, doxazosin is more risky in association with tadalafil, compared with tamsulosin and alfuzosin; some adverse effects may not depend on blood pressure changes only. Thus, the concomitant administration of tadalafil and the non-selective α-adrenergic antagonist doxazosin is contraindicated, whereas concomitant administration of tadalafil and selective α-adrenergic antagonists is possible in certain clinical cases (with necessary precautions).

Other PDE5I therapies (not approved by current guidelines for ED – LUTS/BPH)

Sildenafil

Sildenafil citrate is the first oral agent to be introduced for the treatment of ED. It is rapidly absorbed and has a T_max of approximately 1 h, with a T_1/2 of approximately 4 h. The role of sildenafil in the treatment of LUTS/BPH was initially addressed by preliminary open-label studies. Sairam et al. [36] showed an improvement in urinary symptoms scores in men treated with oral sildenafil for 3 months, especially for patients with lower IPSS at baseline. Mulhall et al. enrolled 48 men with LUTS and found an improvement in IPSS scores after treatment with sildenafil alone. The mean improvement in the EF domain score was 7 points (p = .01); the mean improvement in the IPSS score was 4.6 points (p = .013) and in QoL score was 1.4 points (p = .025). In total, 60% of men improved their IPSS score, and 35% had at least a 4-point improvement in their score, with a mean number of sildenafil pills per week of 2.0 ± 0.6. These preliminary data indicated a positive impact of sildenafil in men with mild-to-moderate LUTS.

It was initially supposed that the medication effect was mediated through bladder neck/prostatic smooth muscle relaxation [37]. Subsequently, larger randomized, double-blind trials (some of which placebo-controlled) were conducted enrolling patients presenting with LUTS with or without ED. McVary et al. gave sildenafil with placebo in men showing IIEF-5 < 25 and IPSS >12, showing an improvement in both indexes as well as BPH-II. However, although some studies showed an increase in Q_max with an increased dose of other PDE5Is, this observation was not significantly different from the placebo group in the study by McVary et al. [38]. Other studies confirmed that the administration of the PDE5i significantly reduced IPSS and led to an improvement in the BPH Impact Index (BPH-II) and QoL. In some protocols, patients presenting with severe LUTS experienced greater improvement in IPSS than those with moderate symptoms. A significant decrease of bladder storage and voiding symptoms during treatment was also noted while residual urine and Q_max did not change significantly. Also, Sildenafil positively impacts on nocturia [39]. These findings suggest that extraprostatic pathophysiological mechanisms related to an impairment in the activity of the nitric oxide (NO) system might also be involved in the onset of LUTS.

Sildenafil was then studied in combination with an α-blocker in various trials. Sildenafil (25 mg once daily) or tadalafil (10 mg once daily) and the α1-adrenoceptor antagonist alfuzosin (10 mg once daily) for the treatment of LUTS were evaluated. Men with untreated LUTS (and concomitant ED) were randomized to either alfuzosin, sildenafil or tadalafil, or the combination of a α-blocker and a PDE5i. Study endpoints were changes from baseline in IPSS, Q_max, Q_ave, and residual urine volume. Improvement in IPSS was significant in all treatment arms, but it was more pronounced with the drug combinations. Residual urine volume, Q_max, frequency, and nocturia improved significantly with alfuzosin only and the combination regimen [40]. Improvements in the IPSS and IPSS-QoL were greater with the drug combination. A study evaluated the efficacy of sildenafil citrate (25 mg, four times per week for 8 weeks), tamsulosin (0.4 mg, once daily for 8 weeks) and the combination of both regimens in 60 men presenting with LUTS/BPH [41]. The authors found that the improvements in IPSS, Q_max and post-voiding residual volume (PRV) were significantly more pronounced in those patients who had received the combination therapy than in those who were on sildenafil citrate only. However, treatment with the drug combination did not enhance the improvements in IPSS and voiding symptoms seen in the tamsulosin group.

The acute administration of sildenafil has been shown to improve Q_max and Q_ave in men with LUTS/BPH. A single dose of the PDE5i (50 mg or 100 mg) resulted in an improvement in Q_max in the patients. Q_ave and the mean voided volumes of the patients also increased, while no significant differences were registered in Q_max, Q_ave, and voided volumes of the control group before and after placebo administration [42,43]. However, these studies were designed with a small number of patients making it rather difficult to draw firm conclusions from these observations.

Additional large-scale, randomized, placebo-controlled studies are needed to further assess the clinical effectiveness of sildenafil and/or α-adrenoceptor blockers to treat ED – LUTS/BPH. Presently, sildenafil is not the first-therapy choice in treating the combined phenotype.

Vardenafil

Vardenafil is rapidly absorbed and its serum peak concentration is reached within an hour (median of 0.7 h). The T_1/2 is 4–5 h. The T_max is not affected by moderate fat intake, but is slightly reduced with a high fat diet [44]. The role of vardenafil for the treatment of LUTS/BPH has not been widely assessed. Stief et al. investigated its effects on LUTS in men with LUTS/BPH with or without ED in a randomized, double-blind, placebo-controlled study. In all, 221 patients aged 45–64 years with an IPSS >12 at the enrollment were randomized to either 10 mg vardenafil or a matched placebo tablet twice daily for 8 weeks. The mean IPSS at baseline was 16.8 and the Q_max was 15.9 ml/s in both groups. The treatment phase with vardenafil was associated with a significant improvement in the IPSS compared with placebo (−5.9 versus  −3.6, respectively, p < .001). The group treated with vardenafil had a significant advantage for obstructive and irritative subscores (p < .008 and <.002, respectively), and for QoL. No difference was reported in the Q_max between the groups. With vardenafil, 29.6% of patients reported adverse events, versus 15.9% in the placebo group. The twice daily dose was overall well tolerated, with most adverse events considered mild or moderate in severity. However, the design of this study received comments about being atypical for a LUTS/BPH study. Limitations of this study were the absence of a run-in period, considered as a standard method in BPH trials, and a Q_max at baseline that was close to normal. Consequently, while this study enlightens that vardenafil may be a promising choice for LUTS/BPH – ED, further studies are needed to better understand whether vardenafil may become a treatment choice for this pathological condition [45].

Avanafil

Avanafil, a new-generation PDE5i, is highly selective for PDE5. It has also relatively little cross-reactivity with other PDE isoenzymes. In an in vitro receptor-binding study comparing the inhibitory effects of avanafil on 11 PDE isoenzymes with those of tadalafil, sildenafil, and vardenafil, avanafil potently inhibited PDE5 activity without significant inhibition of the other PDE isoenzymes. In contrast, tadalafil, sildenafil, and vardenafil inhibited the activity of other PDE isoenzymes (PDE1, PDE6, and PDE11). These differences in PDE isoenzyme activity are important, given that greater selectivity for the PDE5 isoenzyme may diminish the potential for adverse effects (caused by the inhibition of other PDE isoenzymes; e.g. inhibition of PDE6 by other PDE5 inhibitors may lead to visual disturbances) [46].

In single-dose pharmacokinetic studies, avanafil had a time to maximum plasma drug concentration of 30–45 min and a half-life of approximately 3–5 h. Other PDE5i achieve time to maximum plasma drug concentration at approximately 60 (sildenafil and vardenafil) to 120 (tadalafil) minutes after dosing. Phase 2 studies that assessed penile tumescence and rigidity in response to visual stimulation in men with ED found that avanafil, 50, 100, and 200 mg, was statistically superior to placebo, with peak effects occurring 20–40 min after dosing, consistent with the drug’s pharmacokinetic profile. Flushing and headache were again the most common side effects, but usually transient and only mild to moderate. Furthermore, the actual rates of the most common side effects were particularly low (ranging from 1.6 to 3.7%). Fewer than 2% of patients discontinued therapy due to an adverse drug reaction in one study. Interestingly, avanafil had lower rates of hypotensive episodes (15%, 29%, and 12% for avanafil, sildenafil, and placebo, respectively) with monitored co-administration of nitroglycerin in males. This might suggest a possible role for use in patients with concurrent nitrate use, but further studies need to assess this effect. No drug accumulation was observed in multiple-dose pharmacokinetic studies that evaluated once- and twice-daily dosing with avanafil for up to 2 weeks [47]. Therefore, it is possible to suppose that, in relation to low half-life of avanafil, this drug could achieve a minor effect on physiopathological effects of LUTS/BPH compared with other PDE5Is, if not administered multiple times a day. To our knowledge, no studies so far have established a possible role of avanafil in specifically in LUTS/BPH – ED therapy.

Mirodenafil

Mirodenafil (Mvix), a second-generation PDE5i, was launched in Korea in November 2007, and its orally dissolving film (Mvix S) was launched in December 2011. The product is available in tablet formulation or orally dissolving film of 50 and 100 mg. Mirodenafil has been approved only in Korea. Its pharmacokinetic profiles include a T_max of 1.25 h, T_1/2 of 2.5 h and an IC₅₀ for PDE5 of 0.34 nmol/l, which would confer a biochemical property of relatively high affinity (potency) for PDE5. While the pharmacokinetic profile is similar to that of sildenafil, mirodenafil appears to be 10 times more selective for PDE5 than sildenafil.

Several randomized, controlled trials have reported the favorable clinical efficacy and tolerability of mirodenafil in men with ED of a broad range of etiologies or severity. A multicenter, open-label, prospective, non-comparative study by Lee et al. evaluated the efficacy and tolerability of the combination of daily administered α1-blockers (tamsulosin 0.2 mg or alfuzosin) with 100 mg mirodenafil (twice a week) in 121 patients with both LUTS/BPH and ED, who already received stable α1-blocker therapy for more than 3 months [48]. After the start of the study, mean IPSS significantly decreased from 15.6 ± 7.8 at baseline to 11.3 ± 5.8 at 4 weeks and 9.0 ± 4.9 at 8 weeks, and mean quality of life index decreased from 3.2 ± 0.9 at baseline to 2.9 ± 0.9 at 4 weeks and 2.4 ± 1.0 at 8 weeks. Mean IIEF-5 score significantly increased from 7.8 ± 4.3 at baseline to 11.2 ± 4.2 at 4 weeks and 15.2 ± 4.0 at 8 weeks. However, no significant improvement in Q_max or PVR was observed. No significant change in BP or heart rate (HR) was observed during the study. The adverse effects were minimal and self-limited. Another prospective, multicenter, open-label trial assessed the efficacy and tolerability of daily co-administered α1-blocker and 50 mg mirodenafil in patients with both LUTS/BPH and ED, who were already receiving stable α1-blocker therapy for at least 4 weeks. Although the improvement of total IPSS after the initial α1-blocker monotherapy of 4 weeks was significant (from 23.7 to 18.7), the addition of 50 mg mirodenafil to the α1-blocker resulted in further reduction in total IPSS at 4 and 8 weeks after the co-administration (14.3 and 13.7, respectively). In terms of efficacy in the treatment of ED, the mean IIEF-5 scores significantly improved at 4 and 8 weeks after the additional mirodenafil medication (16.2 ± 5.8 and 16.2 ± 5.1, respectively), compared with before the co-administration (10.9 ± 5.7). Although the daily co-administered α1-blocker and 50 mg mirodenafil did not reduce the residual urine, the Q_max improved at the end of the study period. This study also did not report severe or serious adverse events [49].

Udenafil

Udenafil (Zydena) is a PDE5I developed by a Korean pharmaceutical company in 2005, with a pharmacokinetic profile in that its T_max is about 1–1.5 h and its T_1/2 is about 11–13 h. Its molecular structure is similar to that of sildenafil citrate, and the isoenzyme selectivity profile of udenafil is comparable to that of sildenafil. The clinical effect of udenafil is known to last for 24 h or more in clinical practice. Its product is available in tablet formulation of 100 mg and 200 mg. This drug is still not approved except in Korea, Russia, and Philippines, even if in United States phases IIa and III have been conducted since 2006. An open, prospective, non-comparative study by Chung et al. showed an improvement in IPSS, IIEF-5, and no significant changes in blood pressure and heart rate in 120 men, who were already receiving a stable α-blocker therapy, by adding udenafil 100 mg in combination therapy. The incidence of adverse events was similar to earlier reports on monotherapy using PDE-5i in patients with ED, or with monotherapy using α-blockers in patients with LUTS/BPH. Thus, the co-administration of udenafil and α-blockers did not elevate the incidence of such adverse events, so the therapy appeared safe [50].

Effects of drugs used for LUTS on erectile function

Several drugs used for LUTS may strongly affect sexual function. Patients with BPH benefit from treatment with α-blockers in single or combination therapy [51–55]. Also, nutraceutical drugs are used for the prevention of prostate diseases [56]. A recent systematic review and meta-analysis evaluated the impact of combination treatment with α-blockers and/or 5α-reductase inhibitors (5α-ARI) on the risk of ED and libido alterations from randomized clinical trial. Based on the inclusion and exclusion criteria, five studied involving 6131 patients were included in the analysis. According to the analysis, the overall prevalence of ED and libido alteration were significantly greater in the combination treatment group than in the α-blockers group (7.93% versus 4.66%; OR 1.81; p < .0001 and 3.69% versus 2.36%; OR 1.58; p = .003, respectively). The combination therapy increased the risk of ED compared to monotherapy with 5α-ARI (7.93% versus 6.47%; OR 1.25; p = .04), but not the risk of libido alteration (3.51% versus 3.37; OR 1.03; p = .84). Therefore, this meta-analysis showed that the combination therapy with α-blockers and 5α-ARI was associated with significantly higher risk of ED and libido loss compared to monotherapy. The combined treatment showed a similar risk of altering libido compared to 5α-ARI monotherapy [57].

Conclusion

The IPSS and IIEF-5 scores may drive the first drug-therapeutic approach in patients with BPH. In great detail, in the absence of ED (IIEF-5 > 21), patients with an IPSS score <7 may benefit from phytotherapy, whereas those with an IPSS score >7 should undergo on α-blockers therapy. On the contrary, the daily administration of Tadalafil 5 mg may be suggested in those patients with ED (IIEF-5 < 21). Therapy with α-blockers might be offered in those cases with an IPSS score showing a greater severity than the IIEF-5 one. A schematic practical approach to the patient with LUTS/BPH and ED to establish the therapeutic choice is reported in Figure 1.

Figure 1. Flow-chart of a practical andrological evaluation of a patient with benign prostatic hyperplasia to decide first drug-therapeutic approach.

Disclosure statement

No potential conflict of interest was reported by the authors.