Impact of combination therapy 5-alpha reductase inhibitors (5-ARI) plus alpha-blockers (AB) on erectile dysfunction and decrease of libido in patients with LUTS/BPH: a systematic review with meta-analysis

Abstract

Lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO) represent one of the most common clinical complaints in adult men. Several drugs used for LUTS/BPO may strongly affect sexual function and bother. The aim of this systematic review and meta-analysis was to evaluate the impact of combination therapy with alpha-blockers (AB), 5-alpha reductase inhibitors (5-ARI) on the risk of erectile dysfunction(ED) and libido alterations (LA) from randomized clinical trial (RCT). Based on the inclusion and exclusion criteria, five RCTs involving 6131 patients were included in the analysis. According to the analysis, the overall prevalence of ED and LA were significantly greater in the combination treatment group than in the AB group (7.93% versus 4.66%; OR 1.81; p < 0.0001 and 3.69% versus 2.36%; OR 1.58; p = 0.003, respectively). The combination therapy increased the risk of ED compared to monotherapy with 5-ARI (7.93% versus 6.47%; OR 1.25; p = 0.04) but not the risk of LA (3.51% versus 3.37; OR 1.03; p = 0.84). In our systematic meta-analysis, we demonstrated that combination therapy with ABs and 5-ARIs was associated with significantly higher risk of ED and LA compared with single monotherapy. Combination therapy showed similar risk of LA compared with 5-ARI monotherapy.

• BPH
• LUTS
• combination therapy
• dutasteride
• side effects
• alpha-blockers
• erectile dysfunction
• finasteride

Introduction

Lower urinary tract symptoms (LUTS) represent one of the most common clinical complaints in adult men [1]. The prevalence of LUTS increases with age, and estimates vary widely depending on definitions and cohorts studied [1,2]. LUTS have a major impact on health-related quality of life (QoL) [2] and are associated with substantial personal and societal costs [3]. LUTS can be divided into storage, voiding and post micturition symptoms, and have traditionally been related to bladder outlet obstruction (BOO) as a result of benign prostatic obstruction (BPO), which is often caused by benign prostatic enlargement (BPE) resulting from the histologic condition benign prostatic hyperplasia (BPH) [4]. In addition, many other conditions, both urological and not urological, may also contribute to LUTS [4]. Sexual dysfunctions (SD), including decreased libido, erectile dysfunction (ED) and ejaculatory dysfunction (EjD), are also highly prevalent and potentially bothersome for the elderly men [5]. Furthermore, preclinical trials and population-based epidemiological studies underline the associations between LUTS and SD, based on common pathogenetic mechanisms, and coexistence of additional contributing factors, such as chronic inflammation and sex steroid ratio imbalance [6]. Moreover, approximately one in five men with BPH has low total testosterone and there is a well-established relationship between LUTS/BPH and low TT [7]. This issue should be taken into account when considering the use of drug that may potentially have a detrimental impact on sexual function.

The main goals of medical treatments for LUTS/BPH are to provide relief from bothering symptoms, improve QoL and prevent disease progression [8,9]. Alpha-blockers [AB], 5-alpha reductase inhibitors [5-ARI], anticholinergic and their combinations thereof are commonly used in the treatment of male LUTS [8,9]. Moreover, a phospodiesterase-5 inhibitor [PDE5-I], Tadalafil 5 mg once daily, has been recently approved for the same indication [9]. Several drugs used for LUTS/BPH may strongly affect sexual function and bother, with different impact across drug classes and even within the same class. Combination therapy with of 5-ARI and AB is the gold standard for the treatment of moderate-to-severe LUTS secondary to BPH. Many randomized clinical trials (RCTs) have widely analyzed the overall impact of AB and 5-ARI medical treatments for BPH on erectile, ejaculatory and libido function, but only a few have extensively and systematically investigated the treatment related ED and libido alteration (LA) of combination treatment and only a meta-analysis has recently evaluated the impact of medical treatment for LUTS due to BPH on ejaculatory function [10]. The aim of this systematic review and meta-analysis was to evaluate the impact of combination therapy on ED and LA from RCT.

Materials and methods

Inclusion criteria

Randomized controlled trials (RTCs) were required to meet the following inclusion criteria: (i) studied the effect of combination therapy with of 5-ARI and AB in determining the onset of ED or LA; (ii) provided sufficient data for analysis, including the mean values and the standard deviations for the International Index of Erectile Function (IIEF) scores; (iii) the overall occurrence of LA has been detailed; and (iv) the full text of the study could be accessed. If the mentioned inclusion criteria were not met, the studies were excluded from the analysis.

Search strategy

A literature search was performed using the Pubmed, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Review and Web of Science, until December 2015. The retrieved studies were searched to identify RCTs that referred to the effects of combination of AB and 5-ARI treatment of LUTS/BPH on erectile and libido function. The following search terms were used: AB, doxazosin, alfuzosin, terazosin, tamsulosin, silodosin, 5-ARI, dutasteride, finasteride, ED, libido, LUTS and BPH. Abbreviations (AB, 5-ARI, ED, LUTS and BPH) were also searched.

Trial selection

The authors independently identified potentially relevant studies and trials. Together, we discussed each of the RCTs that were included and excluded. We excluded studies that either failed to meet the inclusion criteria or had discrepancies that could not be resolved. The study selection process is diagrammatically presented by in Figure 1.

Figure 1. Flowchart of included studies.

Quality assessment

The quality of the retrieved RCTs was assessed using the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials [11]. All the identified RCTs were included in the meta-analysis regardless of the quality score. The methodological quality of each trial was assessed according to how patients were allocated to the arms of the study, the concealment of allocation procedures, blinding, and data loss because of attrition. The patients were then classified qualitatively according to the guidelines published in the Cochrane Handbook for Systematic Reviews of Interventions Based on the quality assessment criteria. The quality of each study was broadly classified into one of the following three categories: (i) all quality criteria were met (adequate), and the study was deemed to have a low risk of bias; (ii) one or more of the quality criteria were partially met (unclear), and the study was deemed to have a moderate risk of bias; and (iii) one or more of the criteria were not met (inadequate or not used), and the study was deemed to have a high risk of bias.

Data extraction

We independently performed the data extraction for the meta-analysis, which included the following: (i) the name of the first author and the publication year; (ii) the study design and sample size; (iii) the therapy that the patients received; (iv) the duration of follow-up; and (v) the source of the patients.

Statistical analysis

Meta-analysis was conducted to determine the risk of ED and LA in patients treated with AB, 5-ARI or combination therapy. SE[ln(OR)] was calculated through a first-order Taylor series conversion, where SE[ln(OR)] = (1/OR)*SE[OR]. Begg and Egger’s methods were used to assess publication bias. Funnel plots were drawn. Statistical heterogeneity was assessed using the Cochran Q and I² statistics. Specifically, statistical heterogeneity was tested using the chi-square test. If I² ≤50%, the variation between studies was considered to be homogenous, then the fixed effect model was adopted. If I²>50%, there was significant heterogeneity between studies, and the random effects model was used. All p values are 2-tailed, α ≤ 0.05 was considered statistically significant (p ≤ 0.05). The analysis was performed using RevMan software v.5.1 (Cochrane Collaboration, Oxford, UK) and using SPSS version 19 (SPSS Inc, IBM Corp., Somers, NY).

Results

Characteristics of individual studies

Based on the inclusion and exclusion criteria, five RCTs [12–16] involving 6131 patients were included in the analysis. The trial selection process is presented in Figure 1. Characteristics of RCTs included in this meta-analysis are listed in Table 1.

Table 1. Characteristics of RCTs included in this meta-analysis.

Paper	Design	Age	Treatments	Subjects	Sample size	Treatment duration (months)
Lepor et al. 1996	RCT	Finasteride: 65 ± 7 Terazosin: 65 ± 6 Combination: 65 ± 7	Terazosin 10 mg plus Finasteride 5 mg	IPSS of at least 8, a mean peak urinary flow rate ≤15 ml/s and no less than 4 ml/s, with a minimal voided volume of 125 ml, and a mean residual volume after voiding of less than 300 ml	1229	12
McConnell et al. 2003	RCT	62.6 ± 7.3	Doxazosin 4 mg plus Finasteride 5 mg	Men ≥50 years of age, an IPSS≥8 points, and Qmax >5 ml/s and ≥15 ml/s with a minimum voided volume≥125 ml	3042	12
Roerhborn et al. 2010	RCT	66.0 ± 7.05	Tamsulosin 0.4 mg plus Dutasteride 0.5 mg	Men ≥50 years of age with a BPH clinical diagnosis by medical history and physical examination, an IPSS ≥12 points, prostate volume ≥30 cm^3 by TRUS, total serum PSA ≥1.5 ng/ml, and Qmax > 5 ml/s and≥15 ml/s with a minimum voided volume≥125 ml	3221	48
Joo et al. 2012	RCT	Tamsulosin: 65.79 ± 8.87 Dutasteride + Tamsulosin: 65.85 ± 7.77	Tamsulosin 0.4 mg plus Dutasteride 0.5 mg	Age≥40 years; diagnosis of BPH; IPSS ≥13 points; maximal urinary flow rate (Qmax) of 4–15 ml/s in a total voided volume≥150 ml	193	12
Kirby et al. 2003	RCT	Doxazosin: 63 ± 7 Finasteride: 63 ± 7 Doxazosin + Finasteride: 64 ± 7	Doxazosin 4 mg plus Finasteride 5 mg	Aged 50–80 years with BPH and a total IPSS ≥12, Qmax ≥5 ml/s but ≤15 ml/s in a total voided volume of 150 ml or greater, and an enlarged prostate as determined by DRE.	1095	12

Quality of individual studies

Pubmed search and Scopus search retrieved 160 records. All the records were screened, leading to the exclusion of 118 papers, which were not relevant for the purpose of this study. The remaining 27 papers were evaluated in full-text form and 12 were excluded because of being irrelevant. Finally, 15 studies were assessed for eligibility but only five studies were included for the meta-analysis. We found low risk of bias among included studies. Overall, the risk of bias was low for all items of the review authors’ judgments.

Alpha-blockers (AB) plus 5-ARI versus AB alone and risk of erectile dysfunction (ED) and libido alteration (LA)

Five studies including 6131 patients (3089 in the combination group and 3042 in the 5-ARI group) were included in the analysis. Heterogeneity was not found among the trials that evaluated ED (p = 0.74, I²=0%) and LA (p = 0.35, I² =11%). According to the analysis, the overall prevalence of ED and libido alteration were significantly higher in the combination treatment group than in the AB group (7.93% versus 4.66%; OR 1.81; p < 0.0001 and 3.69% versus 2.36%; OR 1.58; p = 0.003 respectively) (Figure 2a–b).

Figure 2. Forest plot comparing the risk of erectile dysfunction (a) and libido alterations (b) in RCT evaluating alpha-blockers versus combination therapy.

Alpha-blockers plus 5-ARI versus 5-ARI alone and risk of erectile dysfunction(ED) and libido alteration (LA)

Four studies including 5956 patients (2991 in the combination group and 2965 in the 5-ARI group) were included in the analysis. Heterogeneity was not found among the trials that evaluated ED (p = 0.12, I²=48%) and LA (p = 0.76, I²=0%). According to the analysis, the combination therapy was found to increase the risk of ED compared to monotherapy with 5-ARI (7.93% versus 6.47%; OR 1.25; p = 0.04) but not the risk of LA (3.51% versus 3.37; OR 1.03; p = 0.84) (Figure 3a–b).

Figure 3. Forest plot comparing the risk of erectile dysfunction (a) and libido alterations (b) in RCT evaluating 5-ARI versus combination therapy.

Alpha-blockers versus 5-ARI alone and risk of erectile dysfunction (ED) and libido alteration (LA)

Four studies including 5956 patients (2947 in the AB group and 2965 in the 5-ARI group) were included in the analysis. Heterogeneity was not found among the trials that evaluated ED (p = 0.81, I²=0%) and LA (p = 0.72, I²=0%). According to the analysis, the AB therapy was found to be associated with reduced risk of ED compared to monotherapy with 5-ARI (4.71% versus 6.47%; OR 0.70; p = 0.003) and of LA (2.30% versus 3.37; OR 0.67; p = 0.01) (Figure 4a–b).

Figure 4. Forest plot comparing the risk of erectile dysfunction (a) and libido alterations (b) in RCT evaluating alpha-blockers versus 5-ARI.

Discussion

It is widely acknowledged that both LUTS/BPH and ED have a negative impact on the QoL among aging men [17,18]. Studies during the past decade have firmly established that ED is a highly prevalent condition among aging men, particularly among men with LUTS associated with BPH [19–22]. LUTS may damage male sexual function by decreasing QoL and many studies have suggested that the two disorders share common pathophysiological pathways [23]. However, BPH is a progressive disease, in fact progression of BPH results in more severe LUTS, as well as other symptoms and episodes such as reduction of urinary flow rate, increased incidence of urinary infection, acute urinary retention (AUR) and increased incidence of surgery for BPH [24,25]. The clinical effects of AB in relieving obstructive symptoms in patients with BPH, by relaxing prostatic smooth muscles, are well defined [12,14]. The 5-ARIs block the action of the 5α-reductase enzymes that convert testosterone into dihydrotestosterone (DHT) (which normally promotes prostate growth) and reduce prostate size to relieve obstructive symptoms [26]. The management of BPH focuses not only on reduction of LUTS, but also on prevention of BPH progression and improvement of QoL. Several studies have demonstrated that the use of 5-ARIs reduces adverse events in the progression of BPH [10,16,26]. Moreover, according to the Medical Therapy of Prostatic Symptoms (MTOPS) study, the risk of AUR was lower in groups treated with finasteride or with the combination of an AB and 5-ARI, compared with groups treated with doxazosin [16]. The MTOPS study also reported that AB monotherapy only delayed BPH-associated adverse events (such as AUR), whereas combination therapy with an AB and a 5-ARI, in patients with a prostate volume ≥ 40 ml, reduced both the risk of adverse events and the need for surgical intervention [16]. Although, combination therapy with an AB and a 5-ARI is theoretically ideal because AB treats biokinetic factors associated with prostatic smooth muscle and 5-ARIs treat anatomical factors associated with BPH, several studies reported higher negative effects of this combination on male sexual function, including retrograde ejaculation or anejaculation, ED and decreased libido with different impact across drug classes and even within the same class. Many RCTs have widely analyzed the overall impact of medical treatments for BPH on sexual function, but only a few have extensively and systematically investigated the treatment-related new onset of ED and decreased libido. In this systematic review and meta-analysis of RCTs of the literature, we evaluated the effect of the ABs, 5-ARIs and their combination on erectile function and libido alteration. Of the 103 studies reviewed, only five RCTs were included, involving 6131 participants. The overall prevalence of ED was of 7.93, 6.47 and 4.66% in patients treated with combination therapy, 5- ARI and AB, respectively. The overall prevalence of altered libido was of 3.69, 3.37 and 2.37% in patients treated with combination therapy, 5-ARI and AB, respectively. The main findings of this analysis are that combination therapy with ABs and 5-ARIs is associated with significant higher risk of ED than monotherapy with either ABs or 5-ARIs (OR = 1.81; p < 0.0001). Moreover, 5-ARI monotherapy has the same risk of the combination therapy of having LA (OR = 1.03; p = 0.84). Analyzing the individual monotherapies, ABs significantly reduce the risk of ED (OR = 0.70; p < 0.01) and LA (OR = 0.67; p = 0.01) compared to treatment with 5-ARIs. The major adverse effects of combination therapy were also observed on the ejaculatory function. In a recent meta-analysis of Gacci et al. [10], combination therapy with AB and 5-ARI was associated with significant higher risk of EjD than monotherapy with either ABs or 5-ARIs. In particular, the authors found that combination therapy with ABs and 5-ARIs resulted in a three-fold increase in the risk of EjD as compared with either monotherapies [10]. However, it is well known that ABs have different profile of adverse events with nonselective drugs being associated with lower risk of EjD [27] but higher risk of vascular-related adverse events [28]. In fact, the analysis of Gacci et al. has confirmed that the risk of EjD was similar with either doxazosin or terazosin and placebo, conversely, tamsulosin and silodosin were associated with significantly higher prevalence of EjD. Moreover, due to the highest selectivity, silodosin was associated with the highest risk of EjD [10]. Several studies have evaluated the safety and efficacy of combining ABs and 5-ARIs [13,16], with greatest improvements in Qmax, IPSS, prostate volume and reduced incidence of having AUR or needing surgical therapy for BPH compared to AB or 5-ARI alone [13,16]. Simultaneously, the same studies report higher rates of adverse effects with combination therapy. In the Combination of Avodart and Tamsulosin (CombAT) study, a multicenter trial on combination therapy with tamsulosin and dutasteride in 4844 men with BPH, the reported rate of ED after 24 months was 3.8% with tamsulosin, 6.0% with dutasteride, and 7.4% with combination therapy [28]. At 24 months, retrograde ejaculation, ejaculation failure, and sexual desire impairment were reported, respectively, in 1.1, 0.8 and 1.7% of patients after tamsulosin; in 0.6, 0.5 and 2.8% after dutasteride; and in 4.2, 2.4 and 3.4% after combination therapy [13]. The data of our meta-analysis confirmed that the combination therapy of AB and 5-ARI is associated with a higher risk of ED but, in addition, 5-ARI monotherapy has the same risk of the combination of having decrease libido. These results could be taken into account during the counseling therapy in patients with LUTS/BPH.

Conclusions

In our systematic meta-analysis, we demonstrated that combination therapy with ABs and 5-ARIs was associated with significantly higher risk of ED and LA compared with single monotherapy. Combination therapy showed similar risk of LA compared with 5-ARI monotherapy. The data of this study are important for both drug selection and patient counseling.

Declaration of interest

The authors have nothing to declare.