A Systematic Review and Meta-analysis on the Use of Phosphodiesterase 5 Inhibitors Alone or in Combination with α-Blockers for Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia

doi:10.1016/j.eururo.2012.02.033

European Urology

Volume 61, Issue 5, May 2012, Pages 994-1003

https://doi.org/10.1016/j.eururo.2012.02.033 Get rights and content

Abstract

Context

Several randomized controlled trials (RCTs) on phosphodiesterase type 5 inhibitors (PDE5-Is) have showed significant improvements in both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in men affected by one or both conditions, without a significant increase in adverse events. However, the results are inconsistent.

Objective

Perform a systematic review and meta-analysis of available prospective and cross-sectional studies on the use of PDE5-Is alone or in combination with α1-adrenergic blockers in patients with LUTS/benign prostatic hyperplasia (BPH).

Evidence acquisition

A systematic search was performed using the Medline, Embase, and Cochrane Library databases through September 2011 including the combination of the following terms: LUTS, BPH, PDE5-Is, sildenafil, tadalafil, vardenafil, udenafil, α-blockers, and α1-adrenergic blocker. The meta-analysis was conducted according to the guidelines for observational studies in epidemiology.

Evidence synthesis

Of 107 retrieved articles, 12 were included in the present meta-analysis: 7 on PDE5-Is versus placebo, with 3214 men, and 5 on the combination of PDE5-Is with α1-adrenergic blockers versus α1-adrenergic blockers alone, with 216 men. Median follow-up of all RCTs was 12 wk.

Combining the results of those trials, the use of PDE5-Is alone was associated with a significant improvement of the International Index of Erectile Function (IIEF) score (+5.5; p < 0.0001) and International Prostate Symptom Score (IPSS) (−2.8; p < 0.0001) but not the maximum flow rate (Q_max) (−0.00; p = not significant) at the end of the study as compared with placebo. The association of PDE5-Is and α1-adrenergic blockers improved the IIEF score (+3.6; p < 0.0001), IPSS score (−1.8; p = 0.05), and Q_max (+1.5; p < 0.0001) at the end of the study as compared with α-blockers alone.

Conclusions

The meta-analysis of the available cross-sectional data suggests that PDE5-Is can significantly improve LUTS and erectile function in men with BPH. PDE5-Is seem to be a promising treatment option for patients with LUTS secondary to BPH with or without ED.

Introduction

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are common conditions in middle-age or older men. LUTS range from mild to severe, depending on their occurrence, and include frequency, urgency, nocturia, incomplete emptying, and weak stream that can strongly worsen the quality of life (QoL). For several years, surgery has represented the gold standard of care for this condition, allowing the relief of urinary symptoms and the consequent improvement in QoL [1].

However, since the 1990s, there has been a substantial shift in BPH management from surgical to medical therapy. The current standard of care for LUTS/BPH includes α-adrenergic blockers, 5α-reductase inhibitors, and phytotherapies, used alone or in combination. These therapies are associated with bothering sexual side effects, however, differing in rate and characteristics between different classes of medications, different medications within the same classes, and different combinations of drugs.

Sexual dysfunction is a highly prevalent comorbidity in aging men with LUTS associated with BPH [2]. Although the underlying mechanisms for the relationship between LUTS and erectile dysfunction (ED) in BPH men are not fully elucidated, common links such as the nitric oxide–cyclic guanosine monophosphate (NO/cGMP) pathway, RhoA/Rho-kinase signaling, pelvic atherosclerosis, and autonomic adrenergic hyperactivity can be potential targets for phosphodiesterase type 5 inhibitors (PDE5-Is) [3].

The pathophysiology of male LUTS is highly complex, multifactorial, and far from being completely understood [3] including an impaired NO/cGMP signaling, an increased RhoA/Rho-kinase pathway activation, pelvic ischemia, autonomic overactivity, and increased bladder/prostate afferent activity. As reported in a recent review [3], all these major mechanisms of BPH LUTS could be counteracted by PDE5-Is. The mechanism of action of PDE5-Is on LUTS includes several potential targets such as prostate, urethra, bladder, and LUTS vasculature [4], [5], [6], [7]. A recent comparative study evaluating PDE5 tissue distribution and activity in the human prostatic urethra, prostate, and bladder from the same patient indicate that in human LUTS, PDE5 is mostly expressed and biologically active in the muscular compartment with the following rank order of activity: bladder neck more than prostatic urethra more than prostate [8]. This selective distribution and activity of PDE5 in LUTS [8], along with inhibition of the RhoA/Rho-kinase contractile mechanism induced by PDE5-I in the bladder [7], could be the mechanistic rationale for the use of PDE5-I treatment to ameliorate the dynamic component (bladder dysfunction and urethral contractions) of male LUTS. The importance of the bladder as a target of PDE5-Is in LUTS is further underlined by the significant improvement of urodynamic parameters in spinal cord injury patients after PDE5-Is administration [1] and the efficacy of PDE5-Is on continence recovery after radical prostatectomy for prostate cancer [9] and therefore in men without the prostate gland. PDE5 is also highly expressed in the LUTS vasculature [10]. Chronic ischemia due to pelvic artery insufficiency, caused by the metabolic syndrome (MetS) or hypertension, can induce functional and morphologic changes in the bladder and prostate that can be restored by the use of PDE5-Is [10], [11]. In addition, a modulation of autonomic nervous system overactivity and bladder/prostate afferent nerve activity by PDE5-Is has also been suggested [12], [13], [14].

Finally, although the exact mechanism of action remains to be clarified, inhibition of PDE5 has been demonstrated to have an effect on several pathogenetic pathways contributing to LUTS.

In 2002, Sairam et al. suggested for the first time that PDE-Is could improve urinary symptom scores in men attending an andrology outpatient clinic for ED [14]. In 2006, Mulhall and colleagues confirmed this evidence in a population of men with comorbid ED and mild to moderate LUTS [15]. The following year, with a randomized double-blind placebo-controlled study on BPH men (with or without ED), McVary et al. conclusively established the emerging role of PDE5-Is as an effective and well-tolerated treatment for LUTS [16]. After this research, several clinical trials investigated the use of PDE5-Is in LUTS/BPH men. At the present time, only 17 reviews on the use of PDE5-Is in LUTS/BPH men are available on PubMed (September 2011), with only 2 systematic reviews published in 2011, without meta-analysis, including data from 5 and 4 randomized controlled trials (RCTs), respectively [17], [18].

The aim of the present systematic review is to summarize and meta-analyze the current literature concerning the use of PDE5-Is in LUTS due to BPH, to determine the relative efficacy and safety of PDE5-Is alone or in combination with α-blockers, and to define the best candidates for this treatment based on clinical features and LUTS severity.

Section snippets

Systematic search strategy

An extensive PubMed, Embase, and Cochrane Library search was performed including the following terms: phosphodiesterase type 5, phosphodiesterase type 5 inhibitors, PDE5, PDE5-I, sildenafil, tadalafil, vardenafil, udenafil, lower urinary tract symptoms, LUTS, benign prostatic hyperplasia, and BPH. Reference lists of relevant articles were hand-searched to identify additional articles, and the “related articles” function in PubMed was used. No “language,” “publication year,” or other limits were

Study characteristics

Of 508 retrieved studies, 497 articles were excluded for different reasons; one unpublished trial was added. Figure 1 summarizes the total flowchart, and Table 1 lists the characteristics of the trials included in the meta-analysis. Among the 12 published studies included, 7 compared the effect of PDE5-Is versus placebo [16], [21], [22], [23], [24], [25], [26], and 5 evaluated the effect of α-blockers versus the combination of PDE5-Is and α-blockers [27], [28], [29], [30], [31] (see also Fig. 1

Conclusions

PDE5-Is are effective and well tolerated either alone or in combination with α-blockers in men with LUTS/BPH in the first 12 wk of treatment. PDE5-Is with α-blockers induce a small improvement in flow rate, whereas PDE5-Is alone fail to do it.

Younger men with lower BMI and severe urinary symptoms seem to be the best candidates for PDE5-Is in terms of improvement of their urinary function. Headache, dyspepsia, and back pain are the most frequently reported AEs after PDE5-Is in men with LUTS/BPH.

References (43)

M. Gacci et al.
Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia
Eur Urol
(2011)
A. Morelli et al.
Atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced RhoA/Rho-kinase signalling hyper-activation
J Sex Med
(2009)
A. Morelli et al.
Vardenafil modulates bladder contractility through cGMP-mediated inhibition of RhoA/Rho kinase signaling pathway in spontaneously hypertensive rats
J Sex Med
(2009)
B. Fibbi et al.
Characterization of phosphodiesterase type 5 expression and functional activity in the human male lower urinary tract
J Sex Med
(2010)
M. Gacci et al.
Vardenafil can improve continence recovery after bilateral nerve sparing prostatectomy: results of a randomized, double blind, placebo-controlled pilot study
J Sex Med
(2010)
A. Morelli et al.
Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats
J Sex Med
(2011)
A. Morelli et al.
Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats
J Sex Med
(2010)
K.T. McVary et al.
Autonomic nervous system overactivity in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia
J Urol
(2005)
D. Behr-Roussel et al.
Vardenafil decreases bladder afferent nerve activity in unanesthetized, decerebrate, spinal cord–injured rats
Eur Urol
(2011)
J.P. Mulhall et al.
Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction
J Sex Med
(2006)

K.T. McVary et al.

Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia

J Urol

(2007)

L. Liu et al.

Phosphodiesterase-5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a systematic review and meta-analysis

Urology

(2011)

A.R. Jadad et al.

Assessing the quality of reports of randomized clinical trials: is blinding necessary?

Control Clin Trials

(1996)

K.T. McVary et al.

Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial

J Urol

(2007)

C.G. Stief et al.

A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia

Eur Urol

(2008)

C.G. Roehrborn et al.

Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study

J Urol

(2008)

H. Porst et al.

Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia

Eur Urol

(2009)

H. Porst et al.

Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial

Eur Urol

(2011)

S.A. Kaplan et al.

Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction

Eur Urol

(2007)

A. Bechara et al.

Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH pilot study

J Sex Med

(2008)

G. Liguori et al.

Efficacy and safety of combined oral therapy with tadalafil and alfuzosin: an integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. preliminary report

J Sex Med

(2009)

Cited by (274)

Summary Paper on the 2023 European Association of Urology Guidelines on the Management of Non-neurogenic Male Lower Urinary Tract Symptoms
2023, European Urology
Lower urinary tract symptoms (LUTS) are common, often bothersome, and have multifactorial aetiology.
To present a summary of the 2023 version of the European Association of Urology guidelines on the management of male LUTS.
A structured literature search from 1966 to 2021 selected the articles with the highest certainty evidence. The Delphi technique consensus approach was used to develop the recommendations.
The assessment of men with LUTS should be practical. A careful medical history and physical examination are essential. Validated symptom scores, urine test, uroflowmetry, and postvoid urine residual, as well as frequency-volume charts for patients with nocturia or predominately storage symptoms should be used. Prostate-specific antigen should be ordered if a diagnosis of prostate cancer changes the treatment plan. Urodynamics should be performed for selected patients. Men with mild symptoms are candidates for watchful waiting. Behavioural modification should be offered to men with LUTS prior to, or concurrent with, treatment. The choice of medical treatment depends on the assessment findings, predominant type of symptoms, ability of the treatment to change the findings, and the expectations to be met in terms of the speed of onset, efficacy, side effects, and disease progression. Surgery is reserved for men with absolute indications, and for patients who fail or prefer not to receive medical therapy. Surgical management has been divided into five sections: resection, enucleation, vaporisation, and alternative ablative and nonablative techniques. The choice of surgical technique depends on patient’s characteristics, expectations, and preferences; surgeon’s expertise; and availability of modalities.
The guidelines provide an evidence-based approach for the management of male LUTS.
A clinical assessment should identify the cause(s) of symptoms and define the clinical profile and patient’s expectations. The treatment should aim to ameliorate symptoms and reduce the risk of complications.
Update on the management of benign prostatic hyperplasia and the role of minimally invasive procedures
2023, Prostate International
Lower urinary tract symptoms due to benign prostatic hyperplasia constitute a substantial burden, affecting the quality of life of those affected by this condition. While watchful waiting and medical management using a wide array of pharmaceuticals can be effective, surgery has been one of the most definite solutions for those highly affected by this condition. Transurethral resection of the prostate (TURP) is the gold standard surgical procedure, but other alternatives using laser (HoLEP and ThuLEP) and robotic water jets (Aquablation) are emerging treatments aimed at reducing postoperative morbidity. Minimally invasive procedures conducted in outpatient settings and under local anesthesia or sedation are increasingly being used, especially in those patients with high surgical risk due to comorbidities. These procedures include prostatic arterial embolization, water vapor thermal therapy (Rezum), prostatic urethral lift (Urolift), temporary implantable nitinol device (TIND/iTIND), and transurethral microwave thermotherapy (TUMT). The evidence supporting these treatments is growing, but some uncertainties remain as to what is the magnitude of their advantages and disadvantages compared to TURP. Innovations in the technologies involved in these new procedures may improve their profile for effectiveness and safety. Moreover, new devices are being investigated for marketing approval. Issues around costs and patients’ preferences are also yet to be elucidated, thus their evolving role needs to be weighed against the aforementioned considerations.
The practical assessment and management of male lower urinary tract symptoms
2022, Surgery (United Kingdom)
Lower urinary tract symptoms (LUTS) are highly prevalent to both males and females and can be significantly troublesome for patients. Thus, knowledge of the assessment, management and prognosis of patients who present with complaints pertaining to this symptom complex is of importance to all healthcare professionals – both in primary and secondary care. In this article, we focus on male LUTS and discuss the importance of utilizing standardized terminology in the description of symptoms and signs relating to LUTS, before proceeding to take the reader on a journey through the diagnostic evaluation to a summary of the myriad of pharmacological and surgical treatment options for this ever-expanding field in urological practice.
Fenofibrate mitigates testosterone induced benign prostatic hyperplasia via regulation of Akt/FOXO3a pathway and modulation of apoptosis and proliferation in rats
2022, Archives of Biochemistry and Biophysics
Benign prostatic hyperplasia (BPH) is one of the most age-related health problems that commonly affect men. Regrettably, many individuals may not respond to current medical therapies or develop resistance to them. Accordingly, this study aimed to uncover how potentially fenofibrate, a lipid lowering agent, can ameliorate the induced BPH in rats. Forty rats were categorized randomly into four groups; the control group was given the vehicle (olive oil); the BPH model received testosterone propionate (20 mg/kg daily; s.c.) for 4 weeks; BPH-induced group received finasteride (10 mg/kg daily; p.o.) and BPH-induced group received fenofibrate (80 mg/kg daily; p.o.). After testosterone administration, both weight and relative weight of the prostate increased. Additionally, testosterone upregulated androgen receptor (AR), 5α-reductase gene expression and increased prostate proliferation. Histopathological examination confirmed that testosterone disrupted the histo-architecture of the prostate and caused marked hyperplasia of glands and stroma. On the other hand, fenofibrate administration reverted most hyperplastic changes of testosterone, it significantly reduced weight, relative weight of the prostate and dihydrotestosterone (DHT) level compared to BPH group. Also fenofibrate significantly decreased AR and 5α-reductase gene expression. Fenofibrate significantly suppressed ps473 Akt expression causing FOXO3a nuclear inclusion, which triggered induction of apoptosis. As well, Bax/Bcl2 ratio and caspase 3 content were significantly enhanced. Fenofibrate significantly diminished cyclin D1 immunoexpression and restored normal histo-architecture. In conclusion, this study emphasizes the preventive effect of fenofibrate in BPH rat model. This can be accredited, at least partly, to inhibiting AR and 5α-reductase expressions, the anti-proliferative, and pro-apoptotic activity of fenofibrate via modulation of Akt/FOXO3a pathway.
Pharmacology of the Prostate in Non-Infectious Diseases
2022, Comprehensive Pharmacology
Prostate smooth muscle contraction and prostate growth are central topics in pharmacology of benign prostatic diseases. Both may drive urethral obstruction in benign prostatic hyperplasia (BPH), resulting in impairments of voiding and bladder emptying, and finally lower urinary tract symptoms (LUTS). Available drugs for medical treatment include α₁-adrenoceptor antagonists and the phosphodiesterase-5 inhibitor tadalafil, improving symptoms and urinary flow by relaxation of prostate smooth muscle, and 5α-reductase inhibitors reducing the risk for progression, complications and surgery by inhibition of androgen-dependent growth. However, improvements by available medications are limited, so that surgery due to BPH is still inevitable in numerous patients. Ongoing experimental and clinical research aims to identify alternatives, and to understand current limitations of medical therapy. Non-adrenergic contractions of prostate smooth muscle recently moved into the focus of preclinical research, as they induce prostate smooth muscle contraction in parallel to α₁-adrenoceptors. At molecular level, connections between regulation of prostate smooth tone and growth become increasingly obvious. This article summarizes principles underlying regulation of prostate smooth muscle contraction and prostate growth, available medications and clinical aspects, and recent attempts to identify novel targets and compounds for inhibition of smooth muscle contraction and proliferation in the prostate.
Early investigational agents for the treatment of benign prostatic hyperplasia’
2024, Expert Opinion on Investigational Drugs

View all citing articles on Scopus

View full text

Review – Benign Prostatic HyperplasiaA Systematic Review and Meta-analysis on the Use of Phosphodiesterase 5 Inhibitors Alone or in Combination with α-Blockers for Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia

Abstract

Context

Objective

Evidence acquisition

Evidence synthesis

Conclusions

Introduction

Section snippets

Systematic search strategy

Study characteristics

Conclusions

Eur Urol

J Sex Med

J Sex Med

J Sex Med

J Sex Med

J Sex Med

J Sex Med

J Urol

Eur Urol

J Sex Med

J Urol

Urology

Control Clin Trials

J Urol

Eur Urol

J Urol

Eur Urol

Eur Urol

Eur Urol

J Sex Med

J Sex Med

Review – Benign Prostatic Hyperplasia
A Systematic Review and Meta-analysis on the Use of Phosphodiesterase 5 Inhibitors Alone or in Combination with α-Blockers for Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia