Role of Phosphodiesterase Type 5 Inhibitor on Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms

Sang Deuk Kim; Jong Kwan Park

doi:10.5534/kja.2011.29.2.91

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Kim and Park: Role of Phosphodiesterase Type 5 Inhibitor on Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms

Original Article

Korean J Androl 2011;29(2):91-100.

Published online: 22 August 2011

DOI: https://doi.org/10.5534/kja.2011.29.2.91

Role of Phosphodiesterase Type 5 Inhibitor on Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms

Sang Deuk Kim, Jong Kwan Park

Department of Urology, Medical School, and Institute for Medical Sciences, Chonbuk National University, and Research Institute and CTC for Medical Device of Chonbuk National University Hospital, Jeonju, Korea

Correspondence to: Jong Kwan Park Department of Urology, Medical School, Chonbuk National University, 634-18, Keumam-dong, Deokjin-gu, Jeonju 561-712, Korea Tel: 02-250-1510, Fax: 02-250-1564 E-mail: rain@chonbuk.ac.kr

Received 28 July 201112 August 2011 Accepted 17 August 2011

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

There is strong evidence from multiple epidemiological studies that benign prostate hyperplasia (BPH) induced lower urinary tract symptoms (LUTS) are correlated with erectile dysfunction (ED). Although a direct causal relationship is not established yet, four pathophysiological mechanisms can explain the relationship. These include alteration in activity of nitric oxide (NO)-cyclic GMP signal pathway, autonomic hyperactivity, increased Rho kinase/Rho A pathway and pelvic atherosclerosis. Androgens have been suggested to have an important role in the maintenance of the functional and structural integrity of the urinary tract. Sexual function should be assessed and discussed with the patient when choosing the appropriate management strategy for LUTS, as well as when evaluating the patient's response to treatment. Multiple large clinical trials have shown an improvement in LUTS after phosphodiesterase-5 (PDE5)-inhibitor treatment. Sildenafil is a pioneer of this clinical trial and appears to improve both erectile function and LUTS in subjects with ED. Basically PDE5 I with long half life is an appropriate candidate, therefore tadalafil and undenafil had been used to evaluate both diseases. Placebo-controlled trials of tadalafil showed improvement of LUTS secondary to BPH, but none of the studies showed a significant effect on urodynamic measures. PDE5 Is, such as sildenafil and tadalafil, increase the concentration of cGMP in plasma and smooth muscle, facilitating erection of the penis, relaxation of the bladder neck and prostate and subsequent bladder emptying. And theses PDE5 Is increase cAMP and cGMP levels and are more highly distributed in the prostate than plasma. These findings may help in the assessment of the feasibility of using PDE5 Is to concurrently treat both LUTS and ED.

Keywords: Phosphodiesterase type 5 inhibitor (PDE5 I), Sexual function, erectile dysfunction (ED), Lower urinary tract symptoms (LUTS)

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Fig. 1.

cAMP and cGMP levels in prostate tissue. (A) cAMP and (B) cGMP levels were significantly higher in prostate tissues of groups 2 (udenafil, 200 mg) and 3 (tadalafil, 20 mg) than group 1 (control). ∗p＜0.05, ∗∗p＜0.01.

Fig. 2.

cAMP and cGMP levels in plasma. (A) cAMP and (B) cGMP levels increased significantly 1 h after TURP in the plasma of groups 2 (udenafil, 200 mg) and 3 (tadalafil, 20 mg), but not group 1 (control). ∗p＜0.01.

Fig. 3.

The prostate tissue-to-plasma (T/P) ratio of the phosphodiesterase type 5 inhibitor (PDE5 I) concentration. The ratio was significantly higher in group 2 (udenafil, 200 mg) than in group 3 (tadalafil, 20 mg).

Table 1.

Clinical evidence of sildenafil and lower urinary tract symptoms

Study	Subjects and entry/ baseline data	Study design	Treatment	Effects
Sairam et al⁴⁶	112 men with ED 18% with LUTS IPSS ＜7: 67%, 8∼9: 26%, 20∼35: 6%	Prospective open-label (evidence level 2b)	On demand	- Improved erections: 81% - Changes in IPSS correlated with sexual function scores - A lower IPSS at baseline predicted higher sexual function scores after treatment
Chang et al⁴⁷	108 men with ED IPSS and IIEF assessed at 3 mo	Retrospective (evidence level 2b)	On demand	- IPSS decreased from 15.8 to 13.3 - Significant inverse correlation between IIEF and IPSS
Mulhall et al⁴⁸	48 men with IPSS ＞10	Open label (evidence level 2b)	100 mg	- Mean improvement in ED: 7; IPSS: 4.6 points; quality of life: 1.4 - Improvement of IPSS in 60% of patients (35% >4
McVary et al⁴⁹	189 sildenafil 180 placebo IIEF ≤25, IPSS ≥12	12-wk, double-blind, placebo-controlled (evidence level 1a)	50 mg increased to 100 mg	points); mild LUTS in 17% - Sildenafil group: significantly greater improvements in IPSS and IPSS quality of life than placebo - Greater improvements in patients with severe/moderate LUTS than in those treated with placebo - Adverse events and study discontinuation due to adverse events greater in sildenafil group
McVary et al⁵⁰	Equal previous study. BMI: obese ≥30, overweight ≥25, normal ＜25 kg/m²	Ad hoc analysis previous study (evidence level 1a)	50 mg increased to 100 mg	- Significantly greater improvements in IPSS and IIEF observed in sildenafil-treated patients versus placebo were independent of BMI

ED: erectile dysfunction, LUTS: lower urinary tract infection, IPSS: International Prostate Symptom Score, IIEF: International Index of Erectile Function, BMI: body mass index.

Table 2.

Clinical evidence of tadalafil and lower urinary tract symptoms derived from clinical trials

Study	Subjects and entry/ baseline data	Study design	Treatment/duration	Effects
McVary et al⁵²	138 tadalafil 143 placebo Stratified by IPSS <20 or ≥20 and prior a-blocker therapy	Prospective, randomized, double-blind, placebo-controlled (evidence level 1a)	5 mg increased to 20 mg after 6 wk; 12 wk	- At 6 and 12 wk, IPSS improvements significantly higher in tadalafil than placebo groups - Withdrawal due to adverse events: placebo 1.4%, tadalafil 3.6%; no changes in urodynamic parameters
Roehrborn et al⁵³	1058 (approximately 200 per group): placebo, four tadalafil doses, stratified by IPSS <20 or ≥20	Prospective, randomized, double-blind, placebo-controlled (evidence level 1a)	2.5, 5, 10, 20 mg; 12 wk	- Significant improvement in the 5-mg group - IPSS increased from 4.9 to 1.8 - Higher doses associated with IPSS improvements but more adverse events
Dmochowski et al⁵⁴	99 tadalafil 101 placebo IPSS 13	Prospective, randomized, double-blind, placebo-controlled (evidence level Ia)	- 20 mg; 12 wk	- Significant improvement of IPSS (mean difference between treatments: 4.2). - No change in urodynamic measures (detrusor pressure at maximal urinary low rate)

IPSS: International Prostate Symptom Score.

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