Administration of daily 5 mg tadalafil improves endothelial function in patients with benign prostatic hyperplasia

Abstract

Introduction: Tadalafil is a promising phosphodiesterase (PDE) 5 inhibitor prescribed for erectile dysfunction (ED). Daily low dose (5 mg) of tadalafil has also been used for the treatment of male lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH). PDE5 inhibitors induce relaxation of smooth muscle cells in the urethra, prostate, bladder neck, and blood vessels. The aim of this study was to investigate the efficacy of tadalafil on vessels endothelial function, in patients with male LUTS symptoms associated with BPH.

Methods: The Institutional Review Board (IRB) approved this clinical study and informed consents had been obtained from 81 BPH patients.

The following male LUTS parameters: international prostate symptom score (IPSS), overactive bladder symptom score (OABSS), voiding volume, max and mean voiding flow on voiding flowmetry examination and post-voiding residual urine (RU) were compared at 0, 1, 3, 6, and 12 months after a daily dose of 5 mg tadalafil.

In addition, erectile function was evaluated by the sexual health inventory for men (SHIM) score and vessels endothelial function and peripheral neuropathy were assessed by the brachial-ankle pulse wave velocity (baPWV), ankle brachial index (ABI), and vibration perception threshold (VPT) at 0, 3, 6, and 12 months after treatment.

Results: The mean age of 81 patients was 66.4 ± 11.4 years old. Their prostate size was 30.2 ± 22.1 ml.

Male LUTS parameters including IPSS, OABSS, and RU showed significant improvement from 1 to 12 months after tadalafil administration. Max and mean voiding flow was significantly increased at 6 months after tadalafil treatment.

The SHIM score showed significant improvement after 3 months. Whilst, the results of baPWV also showed significant improvement from 3 to 12 months. ABI was also significantly improved at 6 months. However, there was no change in the VPT at any time point.

Conclusions: Tadalafil is effective for both male LUTS and ED. It is also shown that tadalafil improves baPWV, which we can conclude that higher vessels elasticity has been obtained. This major finding of this study shows that tadalafil has the potency to improve vessels endothelial dysfunction in patients with BPH.

Keywords:

• Tadalafil
• endothelial function
• male lower urinary tract symptoms
• erectile dysfunction

Introduction

Phosphodiesterase (PDE) 5 inhibitors are medications currently prescribed for erectile dysfunction (ED) treatment. Tadalafil is a long acting PDE 5 inhibitor, and is administered for ED treatment on demand [1–3]. Recently, daily low dose (5 mg) of tadalafil has also been used for the treatment of male lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH) [4–6]. PDE 5 inhibitors induce relaxation of smooth muscle cells in the urethra, prostate, bladder neck [7,8], and blood vessels [9]. These mechanisms are considered to induce improvement in male LUTS. We investigated the efficacy of tadalafil for vessels endothelial function in patients male LUTS associated with BPH.

Aim

The aim of this study is to investigate the efficacy of tadalafil for vessels endothelial function in patients with male LUTS associated with BPH.

Methods

The Institutional Review Board (IRB) had approved this prospective clinical study, and informed consent had been obtained from 81 BPH patients.

The following parameters were obtained from these 81 patients.

1. Male LUTS parameters

   1. international prostate symptom score (IPSS)

   2. overactive bladder symptom score (OABSS)

   3. voiding volume (Vol), max (Max), and mean (Mean) voiding flow on voiding flowmetry examination and post-voiding residual urine (RU)

2. Erectile function

   1. sexual health inventory for men (SHIM) score

      These parameters were compared to, 1, 3, 6 and 12 months after daily 5 mg tadalafil treatment.

3. Endothelial function

   1. brachial-ankle pulse wave velocity (baPWV)

   2. ankle brachial index (ABI)

      The measurements of baPWV and ABI were performed by form PWV/ABI (Omron Health Co, Kyoto, Japan). These data were obtained by measuring the blood pressure of the upper and lower extremities after at least 5 min resting. The baPWV showed arterial stiffness and a marker of vascular damages. Generally, the higher baPWV indicate that the vessels have less elasticity, and the baPWV increases according to age. ABI is a well documented indicator of arterial sclerosis and this is diagnosed when the ABI is less than 0.9.

4. Peripheral neuropathy

   1. vibration perception threshold (VPT)

      VPT was measured at the medial malleolus using a 128 Hz tuning fork by measuring the number of seconds until the patient could no longer feel the vibration after the tuning fork was placed on the medial malleolus. This technique is a very simple and useful examination for peripheral neuropathy in patients with diabetes mellitus (DM) [10,11]. The decline of VRT was defined as less than 10 s.

These results were compared 0, 3, 6, and 12 months after daily 5 mg tadalafil treatment.

Main outcome measures

To investigate the efficacy of tadalafil for male LUTS, ED, vessels endothelial function, and peripheral neuropathy in patients with BPH, each parameter was evaluated and compared with pre-treatment results. The data and statistical significance were analyzed using Stat View for Windows version 5.0 (SAS Institute Inc., Cary, NC) where p < .05 was significant.

Results

The mean age of 81 patients was 66.4 ± 11.4 years old. Their prostate size was 30.2 ± 22.1 ml. As this is a continuing study, the current status of the 81 patients is indicated in Figure 1.

Figure 1. Distribution of patients in this study. Fifty three patients completed 12 months administration of tadalafil, and 24 are currently continuing from 3 to 12 months of treatment. Four patients discontinued the study.

Of the 81 patients, 37 patients (46%) had never received medical treatments for male LUTS before this study. Forty four patients (54%) had been using medication for already male LUTS including alpha-1 blockers and 5 alpha reductase inhibitors for at least 3 months. These patients were not satisfied with the previous treatments and elected to have additional therapy. During the observation period of this study, their current treatments had not been changed, and tadalafil was trialed for male LUTS as add on treatments.

Subjective male LUTS parameters including total IPSS (p < .01) and OABSS (p < .01) were significantly improved from 1 to 12 months after tadalafil administration (Figures 2 and 3). In the objective male LUTS parameters, RU (p < .01) (Figure 4) was significantly decreased by tadalafil. Max and mean voiding flow were significantly increased at 6 months after tadalafil treatment (Figures 5 and 6). However, Vol did not change after tadalafil administration.

Figure 2. Change of total international prostate symptom score (IPSS) pre-treatment and after 5 mg daily tadalafil administration. Score of total IPSS was significantly decreased after tadalafil treatment.

Figure 3. Change of total overactive bladder symptoms score (OABSS) pre-treatment and after 5 mg daily tadalafil administration. Score of total OABSS was significantly decreased after tadalafil treatment.

Figure 4. Change of post-voiding residual urine (RU) pre-treatment and after 5 mg daily tadalafil administration. RU was significantly decreased after tadalafil treatment.

Figure 5. Change of max (Max) voiding flow pre-treatment and after 5 mg daily tadalafil administration. Max was significantly increased at 6 months after tadalafil treatment.

Figure 6. Change of mean (Mean) voiding flow pre-treatment and after 5 mg daily tadalafil administration. Max was also significantly increased at 6 months after tadalafil treatment.

The SHIM score significantly improved after 3 months (Figure 7) and continued improvement at 6 and 12 months.

Figure 7. Change of sexual health inventory for men (SHIM) score pre-treatment and after 5 mg daily tadalafil administration. SHIM was significantly increased after 3 months tadalafil treatment.

The results of baPWV significantly improved from 3 to 12 months (3 and 6 months p < .01, 12 months p < .05) (Figure 8). ABI also significantly improved at 6 months (p < .05) (Figure 9).

Figure 8. Change of brachial-ankle pulse wave velocity (baPWV) pre-treatment and after 5 mg daily tadalafil administration. BaPWV was significantly improved after 3 months tadalafil treatment.

Figure 9. Change of ankle brachial index (ABI) pre-treatment and after 5 mg daily tadalafil administration. ABI was significantly improved at 6 months after tadalafil treatment.

However, VPT was not changed by tadalafil treatments.

Discussion

As men age, age-related comorbidities become problematic. Management of ED and late-onset hypogonadism (LOH) has been shown to be an important issue for aged men [12]. Testosterone replace therapy (TRT) is effective not only for LOH and its comorbidities [13,14], but also for male LUTS [15,16]. Similarly, PDE5 inhibitors are well documented medications for ED [17,18]. Twenty years have passed since the first PDE5 inhibitor (sildenafil) was launched. Its effectiveness and safety have been proven [19]. In addition, it has been shown that, tadalafil, another PDE5 inhibitor, combined with physical activity improved ED without any elevation of testosterone in LOH patients [20]. One can suggest that TRT and PDE5 inhibitors are promising agents for anti-aging in aged men.

The mechanism of PDE5 inhibitors is to increase the penile blood flow by endothelial cells relaxation. Recently, tadalafil has been used in male LUTS treatment for patients with BPH [4–6]. Recent meta-analysis data showed PDE5 inhibitors were a valid treatment option for men affected by bothersome urinary symptoms with or without ED [21]. Furthermore, it has also been reported that alpha-adrenoceptor antagonists and PDE5 inhibitors have yielded encouraging results in LUTS patients with persistent ED [22].

In this study, the efficacy of tadalafil for male LUTS has been proven in both subjective and objective parameters.

In the subjective parameters, IPSS data showed that male LUTS improved immediately by daily 5 mg tadalafil treatments. It is also shown that OABSS notably recovered. OAB is bothersome and its symptoms decrease QOL. Our previous report revealed that aging and OAB were risk factors for severe and moderate ED in men with LUTS [23]. Tadalafil was also reported to be effective for female OAB [24]. There is a possibility that ED and OAB have the same pathological mechanism and may respond to a common treatment strategy. When looking at these findings, we note that tadalafil is an acceptable therapy for both OAB and ED.

In the objective parameters, although Vol did not change after tadalafil administration, Max and Mean voiding flow were significantly increased at 6 months. Notably, RU was significantly decreased by tadalafil. Vol, Max, and Mean obtained by voiding flowmetry examination may have been influenced by voiding timing and patients’ psychological conditions. RU however is considered to be one of the most reliable and objective parameters of voiding functions. Therefore, we conclude that daily 5 mg tadalafil treatment for BPH patients is effective in both subjective and objective male LUTS.

In a recent report, it was indicated that both tadalafil 5 mg once daily and on demand (10 or 20 mg) showed efficacy in patients with ED [25]. The patients in this study were BPH patients with a mean age of 66.4 ± 11.4 years which was significantly older (p < .01, unpaired t-test) than our ED patients in our clinic who had a mean age of 53.0 ± 15.1 years (n = 837). We could surmise that they might not so much care and focus on erectile function. The SHIM score did not change after 1 month, but significantly improved after 3 months of daily 5 mg tadalafil administration. Accordingly, erectile function in these patients did not improve immediately, but gradually and continuously recovered by tadalafil use.

One of the most important and significant new findings of this current study is that baPWV had decreased with daily 5 mg tadalafil administration. BaPWV is one of the parameters for arterial wall stiffness. Generally, the higher the baPWV indicate that the vessels have less elasticity, and baPWV increases relative to age [26].

A pilot study from a small number of ED patients (n = 20) demonstrated tadalafil had improved endothelial function measured by peak systolic velocity (PSV) and flow-mediated dilatation (FMD) after 4 weeks [27]. In another study on 20 patients with the observation period up to 12 weeks, tadalafil was reported to improve vascular endothelial function by improvement of intra-pelvic blood flow in these patients with BPH [28]. Our data were obtained from a larger number of patients and longer observation periods compared with previous studies and our results supported these preliminary 3 months’ findings. In our study, we noted that baPWV significantly improved at 3, 6 (p < .01), and 12 (p < .05) months, which indicated longer tadalafil efficacy. As baPWV increases according to age, we conclude that baPWV at 12 months was elevated compared to that at 6 months. Given this, it seems clear that tadalafil has a potential to improve baPWV which translates to improvement of endothelial dysfunction. The mechanisms of PDE5 inhibitors, including tadalafil are based on relaxation of smooth muscle through the nitric oxide pathway. Although there is a difference of PDE inhibitors affinity in organs, smooth muscle exists in the whole body. This could translate that PDE5 inhibitors could improve endothelial function throughout in the human body. We also note that baPWV which is one of the parameters for arterial wall stiffness has decreased after tadalafil treatments. Therefore, tadalafil is considered to be an acceptable medication not only for male LUTS and ED, but also endothelial dysfunction treatment.

ABI is an indicator of arterial sclerosis and can be measured with baPWV concurrently. Arterial sclerosis is diagnosed when ABI is less than 0.9. According to the mechanism of tadalafil, it may not affect ABI. However, ABI was improved after 6 months of tadalafil treatment (p < .05) in this study. Only one patient in this study indicated arterial sclerosis (ABI = 0.725). The ABI was higher than 0.9 in all other patients. We acknowledge that the current patients might be a low risk group for arterial sclerosis and hence a healthier population where these circumstances may have lead to ABI improvement at 6 months.

VPT is a useful examination to evaluate peripheral neuropathy in patients with DM [10,11]. In the field of sexual medicine, the decline of VPT was an indicator of ED severity in patients with DM [29]. If DM peripheral neuropathy is induced by endothelial dysfunction, tadalafil might improve DM peripheral neuropathy. In this study, 39 patients revealed decreased VPT (<10.0 s). However, VPT did not change significantly throughout the study. We believe that this is because the patients were not DM patients.

Conclusions

Daily 5 mg tadalafil treatment for patients with BPH relieved male LUTS symptoms and ED. In addition, this therapy also has the potential to improve endothelial function. These additional systematic favorable effects with tadalafil were not unexpected when we consider the mechanisms of PDE5 inhibitors.

Disclosure statement

The authors declare no conflict of interest.