Pharmacologic Treatment of Male Stress Urinary Incontinence: Systematic Review of the Literature and Levels of Evidence

doi:10.1016/j.eururo.2007.09.037

European Urology

Volume 53, Issue 1, January 2008, Pages 53-59

https://doi.org/10.1016/j.eururo.2007.09.037 Get rights and content

Abstract

Objective

Stress urinary incontinence (SUI) occurs in men and women. Pharmacologic treatment of female SUI has been beneficiary but the role of drug treatment in male SUI is controversial. This review evaluates the drug classes, the effects of these drugs in trials with male SUI, and the levels of evidence of the individual trials.

Methods

A systematic literature review was conducted searching for studies on male SUI published between 1966 and 2007. In retrieved articles, reference lists were hand-searched to identify additional articles. The level of evidence was judged according to the Oxford classification.

Results

This search found nine articles providing evidence that α-adrenoceptor agonists (ephedrine, phenylpropanolamine, midodrine), β₂-adrenoceptor agonists (clenbuterol), and serotonin-noradrenaline reuptake inhibitors (imipramine, duloxetine) have a potentially beneficial effect on male SUI. Most trials used only small numbers of patients and a mixed study population (men and women). The evidence level of most studies was low due to the lack of randomisation (case series or cohort studies, level 4). In contrast, the first high-level study to provide evidence in the treatment of male SUI was with duloxetine, a selective serotonin and noradrenaline reuptake inhibitor (randomised controlled study, level 1b). However, only one well-designed study has been published so far.

Conclusions

One high-level study with duloxetine in combination with pelvic floor muscle training shows preliminary but promising results in the treatment of male SUI. These results have to be confirmed in larger and well-designed trials to allow definite recommendations for the pharmacologic treatment of male SUI.

Introduction

Urinary incontinence (UI) is a common symptom that affects both men and women. Even though it is not life-threatening, it has a significant impact on patients’ psychosocial well-being [1], [2] and quality of life (QoL) [3]. Compared to continent people, men and women with UI have a higher level of anxiety, lower QoL, and poorer life satisfaction [3]. The majority of epidemiologic studies have been conducted in women, confirming the highly prevalent nature of UI, impact on QoL, and frequency of medical consultations [4]. Therefore, UI might appear a problem predominantly of women. However, a review of prevalence studies estimated UI rates of 11–34% for older men and 3–5% for middle aged or younger men [5]. The male prevalence data have recently been confirmed in large surveys conducted mainly in the United States, where the overall prevalence of male UI was reported to be 12.7–17%, of whom 24.5% had stress UI (SUI) [6], [7].

The International Continence Society defines SUI as the complaint of involuntary leakage on effort, exertion, sneezing, or coughing [8]. SUI is a symptom mainly caused by sphincteric incompetence and usually occurs in women after delivery or pelvic surgery, whereas most cases of male UI occur after prostatectomy. UI after radical prostatectomy is related to intrinsic sphincter deficiency in most patients [9], [10], [11], [12], although detrusor overactivity or compliance abnormalities may also exist [13]. One of the largest studies that evaluated incontinent patients after prostatectomy was published in 2005 and included a total of 146 patients [14]. After video-urodynamic investigation, 139 men (95%) were classified as having SUI and had leakage of contrast media through the bladder neck and urethra during the Valsalva manoeuvre or coughing. Of these patients, 24 (17%) also had detrusor overactivity defined as involuntary detrusor contractions with amplitude of > 15 cm H₂O, and 11 patients (8%) had reduced bladder compliance (compliance < 12.5 ml/cm H₂O).

In general, sphincter deficiency might be caused by damage of smooth muscle cells of the bladder neck or proximal urethra, striated muscle cells of the urethral sphincter, or nerves innervating these anatomic structures. To identify possible drugs that could have a therapeutic effect on male SUI, it is crucial to understand the mechanisms maintaining continence. The urinary continence mechanism is complex, involving the integration of the central and peripheral nervous systems as well as skeletal and smooth muscles. The storage phase of the micturition cycle requires relaxation of the detrusor to allow accommodation of increasing urine volumes at low vesical pressure in conjunction with increased bladder outlet resistance, that is, enhanced tone of the bladder neck, urethra, and pelvic floor [15]. Detrusor relaxation is mainly mediated by β₃-adrenoceptor stimulation via noradrenaline release in the hypogastricus nerve. Increased bladder outlet resistance is provided by (1) smooth muscle cell contraction in the bladder neck and proximal urethra mediated by noradrenaline and α₁-adrenoceptor stimulation and (2) striated muscle cell contraction in the external sphincter and pelvic floor mediated by acetylcholine and nicotine receptor stimulation. The rhabdomyosphincter activity is controlled by the Onuf nucleus in the sacral spinal cord and neurons releasing serotonin and noradrenaline modulate this activity.

Surgical procedures have been the standard treatment of SUI for decades and implantation of the artificial urinary sphincter has been the standard treatment for male SUI after prostatectomy SUI [16]. Recently, duloxetine was introduced for the treatment of female SUI [17]. Drug treatment for SUI aims to increase outflow resistance. Because SUI is a symptom that is commonly considered to occur mainly in women, studies investigating the effects of pharmacotherapy in men are sparse. Additionally, anatomic differences of the lower urinary tract between men and women are believed to be responsible for the different underlying pathophysiologic mechanisms of SUI. Even though drugs act on the same structures of the lower urinary tract in both men and women, gender differences might be relevant. Therefore, treatment data from female populations cannot simply be extrapolated to men. This systematic literature review aims to clarify the drug classes suitable for treatment of male SUI, summarise the results of the individual drug trials, and judge the level of evidence of the available studies.

Section snippets

Methods

A Medline search was conducted for articles published between 1966 and June 2007 using the MeSH terms “drug therapy” and “stress urinary incontinence.” In addition, a PubMed and ISI of Knowledge Web of Science database literature search was performed with the search terms “medical treatment,” “pharmacotherapy,” and “post-prostatectomy incontinence.” The reference list of the retrieved articles was additionally studied to identify any articles published before 1966. Articles were also identified

Results

The literature search revealed studies with potentially beneficial effects for symptoms of male SUI using α-adrenoceptor agonists, β₂-adrenoceptor agonists, or serotonin and noradrenaline reuptake inhibitors. Nine trials were identified using drugs of these three distinct classes and the trials of these drugs formed the basis of this article (Table 1). Only one of these studies included a comparison arm. Studies without a comparison arm make the judgement of placebo effects on and spontaneous

Conclusions

Even though medical treatment of SUI has been investigated mainly in women, some studies do exist for male SUI, especially in patients after radical prostatectomy. Most of these studies do not have the most appropriate design for evaluating the effects of treatment and have a low evidence level (level 4 according to the Oxford classification). The newer drug duloxetine with proven efficacy in female SUI seems to be effective in male SUI as well. Although studies with this compound are limited,

Conflicts of interest

The authors have nothing to disclose.

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Cited by (46)

Use of Duloxetine for Postprostatectomy Stress Urinary Incontinence: A Systematic Review
2021, European Urology Focus
Citation Excerpt :
This is the first SR to include all studies evaluating the efficacy and safety of duloxetine in men with PPSUI. A previous review of pharmacological treatments for male SUI included only three studies regarding duloxetine up until 2007 and reported findings consistent with the present review [26]. Importantly, however, the methodology in the previous review differs significantly from the present SR.
The recommended treatment of postprostatectomy stress urinary incontinence (PPSUI) after failure of pelvic floor muscle training is primarily surgical intervention with a male sling or artificial urinary sphincter. The use of pharmacological therapy in this setting is unlicensed and controversial.
To systematically review the available evidence regarding the efficacy and safety of duloxetine for the treatment of stress urinary incontinence following prostate surgery (radical or endoscopic).
The EMBASE, MEDLINE/PubMed, and Cochrane Central Register of Controlled Trials were searched from inception up until April 17, 2020. All studies evaluating the role of duloxetine in men with PPSUI were included. Two reviewers independently screened all articles, searched the reference lists of retrieved articles, and performed data extraction. The quality of evidence and risk of bias were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE); Cochrane; and Risk of Bias in Nonrandomised Studies of Interventions (ROBINS-I) tools.
The search yielded 234 studies. After excluding duplicates, 140 titles and abstracts were screened, and eight reports (348 patients) were eligible for inclusion in the final review. Duloxetine was assessed in two scenarios: (1) early use to reduce the time to attain continence and (2) treatment of persistent PPSUI. Most men had mild-to-moderate incontinence at baseline. Overall, duloxetine resulted in a mean dry rate of 58% (25–89%), mean improvement in pad number of 61% (12–100%), and mean improvement in 1-h pad weight of 68% (53–90%) at short-term follow-up (mean 1–9 mo; low to moderate certainty of evidence). However, mean adverse event rates were relatively high, and treatment was discontinued in 38% (low certainty of evidence).
Duloxetine has demonstrated good short-term cure and/or improvement in treating men with persistent PPSUI, as well as in reducing the time to attain continence. However, a proportion of men discontinue treatment due to adverse events. The overall certainty evidence is moderate to low, with heterogeneity between studies and methodological limitations. However, we have highlighted the need for further randomised trials with longer follow-up, utilising consistent outcome reporting measures. Despite these limitations, the findings from this review will aid patient counselling regarding this less invasive treatment option, thereby allowing personalisation of care centred around the values and preferences of individual patients.
Duloxetine has good success rates in the short term, in terms of improving incontinence symptoms in men who have undergone prostate surgery. However, some men experience side effects bad enough to require cessation of treatment. Further studies are needed to determine whether duloxetine maintains its effectiveness in the long term.
A cocktail of growth factors released from a heparin hyaluronic-acid hydrogel promotes the myogenic potential of human urine-derived stem cells in vivo
2020, Acta Biomaterialia
Citation Excerpt :
Approximately 13 million Americans and 200 million people worldwide suffer from urinary incontinence [3]. Current therapeutic approaches include pharmacotherapy, sling surgery, and injection of bulking agents [4–10]. Despite the success of these therapies, each approach fails over time because they do not address the underlying cause of neuromuscular damage.
Traditional cell therapy technology relies on the maximum expansion of primary stem cells in vitro, through multiple passages and potential differentiation protocols, in order to generate the abundance of cells needed prior to transplantation in vivo. Implantation of in vitro over-expanded and pre-differentiated cells typically results in poor cell survival and reduced regeneration capacity for tissue repair in vivo. We hypothesized that implantation of primary stem cells, after a short time culture in vitro (passage number ≤p3), in combination with controlled release of relevant growth factors would improve in vivo cell viability, engraftment and tissue regeneration. The goal of this study was to determine whether the release of myogenic growth factors from a heparin-hyaluronic acid gel (hp-HA gel) could enhance in vivo cell survival, in-growth and myogenic differentiation of human urine-derived stem cells (USC) with a corresponding enhancement in graft vascularization, innervation and regenerative properties. Human USC were obtained from healthy adult donors (n = 6), expanded and then mixed with a hp-HA gel containing sets of growth factors known to enhance myogenesis (IGF1, HGF, PDGF-BB), neurogenesis (NGF, FGF) and angiogenesis (VEGF), or a cocktail with a combination of growth factors. Primary cultured USC (p3) mixed with the hp-HA gel and the various combinations of growth factors, were subcutaneously injected into athymic mice. In vivo cell survival, engraftment and functional differentiation within the host tissue were assessed. The implanted grafts containing USC and the growth factor cocktail showed the greatest number of surviving cells as well as increased numbers of cells that expressed myogenic and endothelial cell markers as compared to other groups 4 weeks after implantation. Moreover, the graft with USC and the growth factor cocktail showed increased numbers of blood vessels and infiltrating neurons. Thus, growth factors released in a controlled manner from an hp-HA gel containing USC efficiently improved in vivo cell survival and supported vascularization and myogenic differentiation within the grafts. This study provides evidence for the use of primary USC and growth factors in a hydrogel as a novel mode of cell therapy for the promotion of myogenic differentiation for the treatment of injured muscle tissue.
Cell therapies are a promising treatment option for neuromuscular dysfunction disorders. However, major limitations in cell retention and engraftment after implantation remain a hindrance to the use of stem cell therapy for the treatment of muscle injuries or diseased tissues. Implanted long-term in vitro cultured cells tend to demonstrate low rates of survival and tissue engraftment, lessened paracrine effects, and poor homing and differentiation. Human USC are an easily obtainable stem cell source that possess stem cell characteristics such as a robust proliferative potential, paracrine effects on neighboring cells, and multi-potential differentiation. In this study, we demonstrated that a combination of primary human USC with a cocktail of growth factors combined in a hyaluronic gel was optimal for cell survival and engraftment, including myogenic differentiation potential of USC, angiogenesis and host nerve fiber recruitment in vivo. The present study also demonstrated that the use of primary urine derived stem cells at early passages, without in vitro pre-differentiation, implanted in a hyaluronic-heparin hydrogel containing a cocktail of growth factors, provided an alternative safe site-specific delivery method for cell therapy.
Stress urinary incontinence: An undertreated problem which deserves attention
2019, Current Opinion in Biomedical Engineering
Stress urinary incontinence (SUI) is the involuntary leakage of urine which occurs with sudden increase in abdominal pressure, such as during sneezing, coughing, or laughing. This is a common symptom in women, affecting more than 50% of women and a cause of substantial morbidity. Women and men do not commonly report this symptom to their physicians. This under-reporting may be one of the reasons for undertreatment. In fact, successful treatments exist which decrease or cure SUI, including pelvic floor muscle training and various surgeries but only a small fraction of those with SUI receive treatment.
Postradical Prostatectomy Incontinence
2016, Prostate Cancer: Science and Clinical Practice: Second Edition
Incontinence is a common complication of radical prostatectomy for prostate cancer. For these men, postradical prostatectomy incontinence can significantly affect their health-related quality of life. Urinary incontinence after prostatectomy is predominately sphincter related and can range from a few drops to total leakage. There are a variety of treatment options, which range from conservative therapies such as pelvic floor muscle training to more invasive surgical treatments such as the male sling or the artificial urinary sphincter. According to the European Association of Urology and the International Consultation on Incontinence the gold standard remains the artificial urinary sphincter.
Inhibiting neuropeptide Y Y1 receptor modulates melanocortin receptor- and NF-κB-mediated feeding behavior in phenylpropanolamine-treated rats
2013, Hormones and Behavior
Citation Excerpt :
The mechanism underlying appetite suppression by PPA is related to the release of catecholamine, which exerts its inhibitory effects on NPY-containing neurons (Cheng and Kuo, 2003; Hsieh et al., 2007b; Wellman and Davies, 1992). PPA has been clinically prohibited in the USA due to the risks of myocardial injury and hemorrhagic stroke (Pilsczek et al., 2003), but PPA has an anti-addictive effect (Penzner et al., 2008) and can be used clinically to improve male stress urinary incontinence (Tsakiris et al., 2008) and to prevent weight gain after smoking cessation in patients (Parsons et al., 2009). Therefore, the complex and indeterminate effects of PPA in the brain require additional investigation.
Neuropeptide Y (NPY) and nuclear factor-kappa B (NF-κB) are involved in regulating anorexia elicited by phenylpropanolamine (PPA), a sympathomimetic drug. This study explored whether NPY Y1 receptor (Y1R) is involved in this process, and a potential role for the proopiomelanocortin system was identified. Rats were given PPA once a day for 4 days. Changes in the hypothalamic expression of the NPY, Y1R, NF-κB, and melanocortin receptor 4 (MC4R) levels were assessed and compared. The results indicated that food intake and NPY expression decreased, with the largest reductions observed on Day 2 (approximately 50% and 45%, respectively), whereas NF-κB, MC4R, and Y1R increased, achieving maximums on Day 2 (160%, 200%, and 280%, respectively). To determine the role of Y1R, rats were pretreated with Y1R antisense or a Y1R antagonist via intracerebroventricular injection 1 h before the daily PPA dose. Y1R knockdown and inhibition reduced PPA anorexia and partially restored the normal expression of NPY, MC4R, and NF-κB. The data suggest that hypothalamic Y1R participates in the appetite-suppression from PPA by regulating MC4R and NF-κB. The results of this study increase our understanding of the molecular mechanisms in PPA-induced anorexia.
European association of urology guidelines on assessment and nonsurgical management of urinary incontinence
2013, Actas Urologicas Espanolas
La anterior guía clínica de la Asociación Europea de Urología (EAU) sobre incontinencia urinaria comprendía un resumen de las secciones de la consulta internacional de 2009 sobre la incontinencia. Se tomó la decisión en 2010 de volver a escribir esta guía clínica basándose en una revisión sistemática independiente llevada a cabo por el panel de guías clínicas de la EAU, utilizando una metodología sostenible.
Presentamos una versión resumida de la guía clínica completa sobre la evaluación, el diagnóstico y el tratamiento no quirúrgico de la incontinencia urinaria, con el objetivo de aumentar su difusión.
La valoración de la evidencia incluyó una revisión pragmática de las revisiones sistemáticas existentes y nuevas búsquedas bibliográficas independientes, basadas en cuestiones sobre población, intervención, comparador y resultados. La evaluación de los trabajos fue realizada por un panel internacional de expertos, quienes también colaboraron en una serie de debates de consenso, para desarrollar breves resúmenes de evidencia estructurada y recomendaciones basadas en la acción utilizando un sistema modificado de Oxford.
La versión completa de la guía clínica está disponible online (http://www.uroweb.org/guidelines/online-guidelines/). La guía clínica incluye algoritmos que remiten de nuevo al lector a la evidencia de apoyo y son más inmediatamente utilizables en la práctica clínica diaria.
Esta nueva guía clínica presenta un resumen actualizado de la evidencia disponible, junto con claros algoritmos clínicos y recomendaciones basadas en la acción fundamentadas en la mejor evidencia disponible. Cuando dicha evidencia no existe presentan un consenso de opiniones de expertos.
The previous European Association of Urology (EAU) guidelines on urinary incontinence comprised a summary of sections of the 2009 International Consultation on Incontinence. A decision was made in 2010 to rewrite these guidelines based on an independent systematic review carried out by the EAU guidelines panel, using a sustainable methodology.
We present a short version of the full guidelines on assessment, diagnosis, and nonsurgical treatment of urinary incontinence, with the aim of increasing their dissemination.
Evidence appraisal included a pragmatic review of existing systematic reviews and independent new literature searches, based on Population, Intervention, Comparator, Outcome questions. Appraisal of papers was carried out by an international panel of experts, who also collaborated on a series of consensus discussions, to develop concise structured evidence summaries and action-based recommendations using a modified Oxford system.
The full version of the guidelines is available online (http://www.uroweb.org/guidelines/online-guidelines/). The guidelines include algorithms that refer the reader back to the supporting evidence, and they are more immediately useable in daily clinical practice.
These new guidelines present an up-to-date summary of the available evidence, together with clear clinical algorithms and action-based recommendations based on the best available evidence. Where such evidence does not exist, they present a consensus of expert opinion.

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Review – IncontinencePharmacologic Treatment of Male Stress Urinary Incontinence: Systematic Review of the Literature and Levels of Evidence

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Conclusions

Conflicts of interest

J Urol

J Urol

J Urol

Urology

Eur Urol Suppl

Urology

Urology

Eur Urol

Eur Urol

Eur Urol

J Urol

Int J Gynaecol Obstet

Eur Urol

Eur Urol

J Affect Disord

One hundred and fifty men with urinary incontinence. III. Psychosocial consequences

Scand J Prim Health Care

A review of the psychosocial predictors of help-seeking behaviour and impact on quality of life in people with urinary incontinence

J Clin Nurs

Urinary incontinence and psychological distress among older adults

Psychol Aging

Epidemiology and natural history of urinary incontinence

Variation in estimate of UI prevalence in the community: effects of different in definition, population characteristics and study type

J Am Geriatr Soc

Informal care giving time and costs for urinary incontinence in older individuals in the United States

J Am Geriatr Soc

Review – Incontinence
Pharmacologic Treatment of Male Stress Urinary Incontinence: Systematic Review of the Literature and Levels of Evidence