The role of phosphodiesterase type-5 inhibitors in treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia

Abstract

Phosphodiesterase type-5 (PDE-5) inhibitors are approved as the first line of therapy for the treatment of erectile dysfunction. However, different studies have been performed to study the use of these agents in other areas of urology. There are many studies related to the use of PDE-5 inhibitors as a monotherapy or combination therapy with alpha-blockers for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). It has been shown that contractions induced by various agents or electrical field stimulation in organ bath models of prostatic tissue can be reversed by PDE-5 inhibitors. Age, body mass index and the severity of LUTS are important factors for the selection of patients suitable for this treatment. It has also been reported that the use of PDE-5 inhibitors can relieve the chronic pelvic ischemia and endothelial dysfunction associated with metabolic syndrome. Most of the side effects observed with PDE-5 inhibitors are minimal and tolerable. The use of PDE-5 inhibitors is absolutely contraindicated in patients taking nitrate preparations. A significant interaction has not been observed even when a patient is taking several antihypertensive agents concurrently. Co-administration of alpha-blockers and PDE-5 inhibitors may result in orthostatic hypotension; therefore, patients should be stable on α-blocker therapy before the initiation of the combination therapy, and the initial PDE-5 inhibitor dose should be the lowest possible. In this review, our aim was to evaluate the role of PDE-5 inhibitors in the treatment of LUTS associated with BPH by analyzing the current literature.

Introduction

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are bothersome and highly prevalent in men >50 years.^[1,2] The following hypotheses are under investigation to explain the relationship between LUTS and erectile dysfunction (ED): (i) increased Rho-kinase activation^[3], (ii) nitric oxide synthase (NOS)/nitric oxide (NO) level decrease or alteration^[4], (iii) atherosclerosis affecting the small pelvis^[5] and (iv) autonomic nervous system (ANS) hyperactivity.^[6] Investigation of these mechanisms and the effect of therapeutic agents, such as PDE inhibitors, on these pathways may provide new treatment options for both ED and LUTS.

The cycle of normal micturition is a complex neuromuscular process involving the bladder, prostate and urethra and the vascular and neurogenic support of these organs. Various adrenergic, cholinergic, and nonadrenergic noncholinergic neurotransmitters released from nerve terminals and endogenous factors released from vascular endothelial sources are responsible for the smooth muscle tone in the lower urinary tract (LUT). The nitric oxide/cyclic guanosine monophosphate signaling pathway and enzymes related to that pathway, such as phosphodiesterase type-5 (PDE-5), seem to play an important role in the relaxation of the smooth muscle of the LUT. PDE inhibitors contribute to the treatment of LUTS by restricting the degradation of the second messenger cyclic GMP. The distribution and functional significance of PDE enzymes vary in different tissues of the LUT. PDE-4 and 5 dominantly appear in the prostate, PDE-1 and 4 are thought to affect the detrusor smooth muscle function, and PDE-5 may be functionally important in the urethra and vasculature.^[7–10] Furthermore, Uckert et al.^[7] determined the expression of PDE-1, 2, 4, 5, 7, 8, 9 and 10 in the prostate. Therefore, based on the activity of PDE-5 detected in the prostate, PDE-5 inhibitors were assessed for their therapeutic effects on BPH; beneficial effects of the PDE-5 inhibitors, such as sildenafil and tadalafil, on the symptoms and quality of life of men with LUTS, erectile dysfunction, and BPH have also been demonstrated.^[11–13] The aim of this review is to present an update on the role of PDE-5 inhibitors in the treatment of LUTS associated with BPH.

Results of basic research studies

The expression of various PDE isoenzymes in prostate tissue has been documented by the agency of molecular biological methods by Uckert et al.^[14] PDE isoenzymes were isolated by a reverse transcription polymerase chain reaction (RT-PCR) and anion exchange chromatography. Macroscopically normal, nontumorous prostatic tissues of patients who had undergone radical surgery for prostate carcinoma were used for a basic research study. Although, messenger RNA transcripts encoding PDE-1, 2, 4, 5, 7, 8, 9 and 10 in the various anatomical regions of the prostate were detected, only PDE-4 and 5 were found to have hydrolytic activity in the cytosolic and microsomal fractions.^[14] As a result, the authors concluded that PDE-4 and 5 inhibitors may be a therapeutic option for the treatment of urinary obstructions related to BPH.

Phosphodiesterase type-4 was detected in the stromal and glandular areas of the transitional zone by means of laser fluorescence microscopy.^[7] However, immunoactivities of PDE-5 and PDE-11 were detected in the glandular and subglandular areas. These findings were also presented as supportive data for the hypothesis of a justification for the use of PDE inhibitors in the treatment of BPH and LUTS.^[7]

The effects of different PDE-5 inhibitors (sildenafil, vardenafil, and tadalafil) and PDE-4 inhibitors (rolipram and RP 73401) with increasing concentrations on the tension induced by norepinephrine were analyzed by using the organ bath technique.^[15] The tissues were obtained from specimens of patients who underwent surgery for cancer of the prostate or bladder. After exposure of the tissue strips to norepinephrine, PDE-5 and PDE-4 inhibitors were added to the bath. The maximal reversion of tension was obtained with tadalafil.^[15] The findings of this study were presented by the authors as the potential mechanism by which PDE inhibitors can impact LUTS and BPH.

The effect of specific PDE inhibitors (PDE 1, 2, 4 and 5 inhibitors) on the contraction of prostatic tissue induced by a vasoconstrictor peptide (endotethelin-1) were also analyzed by the organ bath technique. Rolipram and tadalafil appeared to be the most effective agents to reverse the tension caused by endothelin-1.^[16]

The effect of vardenafil, a PDE-5 inhibitor, in a bladder outlet obstruction (BOO) model was investigated. The contractile response of bladder strips to electrical field stimulation (EFS), carbachol and potassium chloride (KCl) was determined for different experimental groups. Chronic treatment with a high dose of vardenafil was found to be protective against BOO-induced contractile dysfunction by carbachol.^[17]

Beamon et al.^[18] investigated whether sildenafil citrate can inhibit the functional and structural changes of the detrusor in relation to BOO in a murine model. They demonstrated the preventive effects of oral sildenafil treatment for 6 weeks on detrusor hyperactivity and the increase in detrusor muscle hypertrophy and collagen deposition associated with BOO.

Effects of PDE-5 inhibitors in LUTS/BPH

Lower urinary tract symptoms and ED are common problems in aging males. A relationship between these clinical conditions has been proposed. Basic and translational research efforts have provided new medical approaches for the treatment of LUTS associated with BPH.^[19] The relationship between storage and voiding dysfunction and benign prostatic obstruction due to prostatic enlargement may develop on the basis of the bladder dysfunction associated with prostatic enlargement or hyperplastic enlargement as a biomarker for generalized LUT dysfunction.^[20] The current approach for medical management of LUTS associated with BPH depends on the usage of alpha-1 receptor blockers, such as alfuzosin, doxazosin, silodosin, tamsulosin and terazosin or suppression of the hormonal growth of the prostate by the 5-alpha reductase inhibitors finasteride and dutasteride.^[21]

The effect of sildenafil on LUTS/BPH was initially demonstrated by preliminary open-labeled reports.^[22,23] These studies indicated a positive effect of sildenafil on LUTS/BPH. A larger randomized, double-blind study on the efficacy of sildenafil that included patients with LUTS, either with or without ED, further supported the data obtained from the initial studies.^[24] The improvement of erectile function and LUTS by treatment with sildenafil citrate was thought to be associated with improved quality of life and treatment satisfaction. An improvement in urinary flow rates was not detected.^[24] The authors concluded that there may be a new basic pathophysiologic mechanism underlying the relationship between ED and LUTS/BPH.^[24] Tuncel et al.^[25] compared 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 BPH/LUTS. Although an improvement in the International Prostate Symptom Score (IPSS) was detected in all groups, the improvement of IPSS in the combination and tamsulosin only groups were more prominent in comparison with the sildenafil citrate only group (40.1%, 36.2% and 28.2%, respectively). The improvement of the maximum urinary flow rate (Qmax) was found to be similar in the sildenafil citrate and tamsulosin only groups; however, a significant improvement was observed in the combination group compared with the other groups. Furthermore, the reduction of post void residual urine volume (PVR) was significantly greater in the combination and tamsulosin only groups. The authors concluded that treatment with the combination of sildenafil citrate and tamsulosin was not superior to tamsulosin only for improving voiding symptoms.^[25] There is a need for additional, large-scale, randomized, placebo-controlled studies to assess the clinical effects of combination therapies. The acute administration of sildenafil was shown to have a significant effect on urinary flow rates.^[26,27] Single-dose (50–100 mg) use of sildenafil citrate seems to provide a significant increase in the Qmax and average urinary flow rate as well as the mean voided volume.

The efficacy of vardenafil twice daily treatment in the management of LUTS/BPH was assessed in a randomized, placebo-controlled study.^[28] A significant improvement was indicated by the IPSS, International Index of Erectile Function (IIEF) and quality of life-9 (QoL) scores. No significant change was observed for Qmax or PVR in patients with vardenafil treatment. Consequently, vardenafil treatment was presented as a promising option for LUTS/BPH.^[29]

Double-blind randomized, placebo-controlled clinical studies to evaluate the effect of different doses of tadalafil on LUTS/BPH revealed a significant improvement in IPSS scores.^[29–32] A significant improvement in the urinary flow rate was not reported. However, only Egerdie et al.^[30] reported a significant increase of Qmax with a 2.5 mg daily dosage of tadalafil compared to placebo (1.7 mL/s vs. 1.2 mL/s, respectively).

A recent randomized, double-blind, international, placebo-controlled, parallel-group study assessed men ≥45 yr of age with LUTS/BPH, an International Prostate Symptom Score (IPSS) ≥13, and a maximum urinary flow rate (Qmax) ≥4 to ≤15 mL/s.^[33] As a primary objective, the effect of the 5 mg once daily dosage of tadalafil on LUTS/BPH was compared with placebo. The secondary objective was to compare tamsulosin, an alpha blocker that is often used as a first-line treatment for LUTS/BPH, with placebo as an active control. Although, tadalafil and tamsulosin were not directly compared in this study, monotherapy with tadalafil or tamsulosin was found to have a significant effect on LUTS/BPH and Qmax versus placebo.^[33]

Impairment of the blood supply of the prostate is one proposed mechanism that is under investigation to explain the relationship between BPH/LUTS and ED. Some studies have shown that the impairment of the perfusion of the transition zone of the prostate was significantly lower and the mean flow resistance index was significantly higher in men with BPH versus healthy subjects.^[34–36] These findings may indicate that regular usage of PDE-5 inhibitors may improve the vascular supply of the prostate and be beneficial for the medical management of BPH/LUTS.

To our knowledge, studies examining the efficacy and the adverse effects of the combination therapy of PDE-5 inhibitors with 5-alpha reductase inhibitors have not yet been published.

The improvement of the LUTS seems to be highly associated with the scoring of the baseline IPSS: a better response to the treatment can be obtained with the PDE-5 inhibitors in cases with higher baseline scores.^[37] The effectiveness of PDE-5 inhibitor treatment for BPH/LUTS also seems to depend on age and body mass index (BMI). Younger men with low BMI and more serious urinary symptoms have been presented as the best candidates for PDE-5 inhibitor treatment.^[37]

Metabolic syndrome and its components, such as diabetes, hypertension and obesity, have major impacts on the quality of life of patients and have socio-economic implications.^[38] Although there is no direct medical treatment for metabolic syndrome, lifestyle changes, such as diet modification and increased physical activity, have been shown to be related with an improvement in endothelial function resulting in a reduction in the vascular complications of metabolic syndrome, such as ED. Chronic ischemia caused by pelvic atherosclerosis and the functional and morphologic changes in the bladder and prostate in relation to metabolic syndrome and its components can be restored by the use of PDE-5 inhibitors.^[39,40] Additionally, autonomic nervous system hyperactivity, which is considered to be one of the factors underlying the relationship between LUTS and ED, can be modulated by the use of PDE-5 inhibitors.^[41,42]

The current data do not suggest a relationship between the efficacy of PDE-5 inhibitor treatment and prostatic volume, prostate-specific antigen value, acute urinary retention or the need for surgical intervention.^[37]

Treatment with PDE-5 inhibitors has not been covered yet by insurance policies for certain indications in Turkey. A retrospective study, including patients who were recommended to take PDE-5 inhibitors for ED complaints, revealed that 10.7% of patients never used the medication and 50% could not continue due to its high cost.^[43] After the expansion of the scope of insurance policies, more patient compliance can be achieved in the treatment of ED and other urological disorders. Additionally, successful communication with the patient may be necessary to ensure the continuity of treatment.

Safety

Flushing, headache, dyspepsia, and back pain are the most frequently observed side-effects of PDE-5 inhibitor treatment.^{[24,28,29,32]} The usage of PDE-5 inhibitors with organic nitrates and other nitrate preparations used to treat angina, as well as amyl nitrite or amyl nitrate is absolutely contraindicated.^[44] The side-effects of a PDE-5 inhibitors are not worsened by antihypertensive therapy, even when patients are taking several antihypertensive agents.^[44] Under some conditions, co-administration of alpha-blockers and PDE-5 inhibitors may result in orthostatic hypotension. Therefore, patients should be stable on α-blocker therapy before the combination therapy is initiated, and the initial dose of PDE-5 inhibitors should be the lowest possible.^[44]

In conclusion; the usage of PDE-5 inhibitors for the management of various urogenital disorders comes into question with the growing knowledge of the mechanisms controlling the urogenital system. PDE-5 inhibition results in smooth muscle relaxation and increased pelvic blood perfusion in these tissues and likely modulates afferent nerve activity. This might represent a novel approach in addition to the first line medical treatment for BPH/LUTS. Furthermore, the combination of PDE-5 inhibitors with an alpha-adrenoceptor antagonist or antimuscarinic agent may affect multiple peripheral targets of the urogenital tract. Combination therapy with alpha-blockers may lead to orthostatic hypotension. There is a need for randomized controlled trials to analyze the efficacy and side-effects of combination therapy with PDE-5 inhibitors and 5-alpha reductase inhibitors. Age, BMI and LUTS severity seem to be important parameters in determining the most appropriate candidates for PDE-5 inhibitor treatment. Pelvic atherosclerosis associated with metabolic syndrome can be restored by PDE-5 inhibitor treatment.