Stesura Seveso Archivio Italiano di Urologia e Andrologia 2022; 94, 2252 REVIEW No conflict of interest declared. INTRODUCTION Alpha adrenergic receptor (or adrenoreceptor) antago- nists, also known as alpha-blockers, are a class of phar- macological agents acting as antagonists on various alpha- adrenergic receptors. Depending on receptor specificity, they bind and inhibit alpha1-receptors, alpha2-receptors, or both (1). Alpha-1 adrenergic antagonists bind to type-1 alpha- adrenergic receptors, thus inhibiting smooth muscle con- traction. Several subtypes of postsynaptic alpha1 recep- tors are present in vascular and nonvascular smooth mus- cle. Alpha 1A receptors are predominantly located in the smooth muscle of the genitourinary tract, where they reg- ulate the tone of the bladder neck and of the smooth mus- cle fibers within the prostate. Alpha 1B receptors are more represented in the vascular smooth muscle, and are involved in the regulation of the vascular tone. Receptors belonging to the alpha1D subtype regulate the contrac- tion of the urinary bladder (2). The effects of alpha- Background: Alpha-adrenoreceptor antago- nists or alpha-blockers are used in the treat- ment of hypertension, in the therapy of benign prostatic hyper- plasia and in medical expulsive treatment of ureteral stones. These agents may affect the sexual function, with differences between drugs within the same class, depending on their selec- tivity for receptor subtypes. The aim of this review was to ana- lyze the effects of alpha-blockers on sexual function. Materials and methods: We conducted a systematic review and meta-analysis by searching PubMed, EMBASE and other data- bases for randomized controlled trials (RCTs) reporting sexual adverse effects in patients treated with alpha-blockers. Odds ratios for sexual dysfunction were calculated using random effects Mantel-Haenszel statistics. Results: Out of 608 records retrieved, 75 eligible RCTs were included in the meta-analysis. Compared with placebo, alpha- blockers were associated with increased odds of ejaculatory disorders both in patients with lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia (BPH) (OR: 7.53, 95% CI: 3.77-15.02, Z = 5.73, p < 0.00001, I2 = 55%) and in patients with ureteral stones (OR: 2.88, 95% CI: 1.50-5.44, Z = 3.19, p < 0.001, I2 = 31%). Uroselective alpha-blockers showed higher odds of ejaculatory disorders. Conversely, nonselective alpha-blockers were not associated with higher odds of ejaculatory dysfunction. Silodosin was associated with increased odds of ejaculatory dysfunction compared with tamsulosin (OR: 3.52, 95% CI: 2.18-5.68, 15 series, 1512 participants, Z = 5.15, p < 0.00001, I2 = 0%). Naftopidil and alfuzosin showed lower odds of ejaculatory dysfunction compared to uroselective alpha-blockers. Effect of alpha-adrenoceptor antagonists on sexual function. A systematic review and meta-analysis Rawa Bapir 1, 13, Kamran Hassan Bhatti 2, 13, Ahmed Eliwa 3, 13, Herney Andrés García-Perdomo 4, 13, Nazim Gherabi 5, 13, Derek Hennessey 6, 13, Vittorio Magri 7, 13, Panagiotis Mourmouris 8, 13, Adama Ouattara 9, 13, Gianpaolo Perletti 10, 13, Joseph Philipraj 11, 13, Alberto Trinchieri 12, 13, Noor Buchholz 13 1 Smart Health Tower, Sulaymaniyah, Kurdistan region, Iraq; 2 Urology Department, HMC, Hamad Medical Corporation, Qatar; 3 Department of Urology, Zagazig University, Zagazig, Sharkia, Egypt; 4 Universidad del Valle, Cali, Colombia; 5 Faculty of Medicine Algiers 1, Algiers, Algeria; 6 Department of Urology, Mercy University Hospital, Cork, Ireland; 7 ASST Nord Milano, Milan, Italy; 8 2nd Department of Urology, National and Kapodistrian University of Athens, Sismanoglio Hospital, Athens, Greece; 9 Division of Urology, Souro Sanou University Teaching Hospital, Bobo-Dioulasso, Burkina Faso; 10 Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; 11 Department of Urology, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India; 12 Urology School, University of Milan, Milan, Italy; 13 U-merge Ltd. (Urology for emerging countries), London-Athens-Dubai *. Authors 1-12 have equally contributed to the paper and share first authorship. *U-merge Ltd. (Urology for Emerging Countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. U-merge Ltd. is registered with the Companies House in London/ UK. www.U-merge.com. DOI: 10.4081/aiua.2022.2.252 Summary No statistically significant differences in the odds of erectile dys- function were observed when alpha-blockers were compared to placebo. KEY WORDS: Alpha-blockers; Ejaculation; Erectile dysfunction; Silodosin; Tamsulosin; Alfuzosin; Doxazosin; Terazosin. Submitted 11 February 2022; Accepted 24 March 2022 253Archivio Italiano di Urologia e Andrologia 2022; 94, 2 Sexual function and alpha-blockers adrenergic blocking agents depend on their selectivity (or non-selectivity) for specific receptor subtypes. Nonselective alpha-1-adrenergic antagonists have been used for decades against hypertension. Blockade of alpha1B receptors can decrease vascular resistance in peripheral arterioles and increase venous capacitance, ultimately lowering blood pressure (3). At present, alpha1 adrenergic antagonists are no longer recommend- ed as monotherapy, but only as adjunctive treatment of hypertension (4). Alpha-1-blockers are used for the treat- ment of symptoms of urinary obstruction due to benign prostatic hyperplasia because they can relax the smooth muscle fiber in the bladder neck and in the prostate act- ing on alpha1A receptors. Initially, nonselective alpha-1 adrenergic antagonists such as doxazosin, terazosin and alfuzosin were used for the management of bladder neck obstruction (5). Selective alpha1A blockers with high affinity for the alpha1A adrenergic receptor, as tamsu- losin and silodosin, have been subsequently developed to be specifically used in benign prostatic hyperplasia. Selectivity of these agents was aimed at decreasing their effect on blood pressure and at reducing the risk of unwanted effects, such as postural hypotension. Alpha1D-adrenoceptor antagonists have also been shown to be effective in alleviating both voiding and storage LUTS associated with BPH. Naftopidil is an alpha-1 adrenoceptor antagonist with a distinct selectivity for the alpha1D receptor showing a threefold selectivity for the alpha1D-adrenoceptor compared to the alpha1A-adreno- ceptor (6). It is used for BPH management in Japan because of its fewer side effects, but there is limited evi- dence of its effectiveness in other populations (7). Alpha-1-adrenergic antagonists are also used to facilitate the spontaneous passage of stones in the distal ureter. When alpha-1-adrenergic antagonists are administered for benign prostatic hyperplasia and for medical expul- sive therapy, their effect at various sites of the uro-genital tract may affect sexual function, with differences between drugs within the same class. The aim of this study is to review the existing evidence on the effect of alpha-1-adrenergic antagonists on sexu- al function. MATERIALS AND METHODS The review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- Analyses) guidelines (8). It was registered on the PROS- PERO platform as CRD42021283385. We included in this review randomized controlled trials (RCTs), with single/double blinded design involving par- ticipants of any age or ethnicity who were treated with alpha adrenergic receptor antagonists for different condi- tions such as arterial hypertension, bladder neck obstruc- tion by benign prostatic hyperplasia (BPH) or ureteral obstruction by ureteral stones (medical expulsive treat- ment or MET). The following outcomes were considered: (i) rate of ejac- ulatory disorders, (ii) rate of erectile disorders, (iii) scores of tests measuring erectile (IIEF-5) or ejaculatory activity (MSHQ-EjD, DAN-PSSsex). Two electronic databases (PubMed and EMBASE) were searched for articles published up to September 30th, 2021. Database interrogation was performed using spe- cific search strings; for example, the PubMed search was preferentially based on MeSH terms {('adrenergic alpha- antagonists'/exp OR 'adrenergic alpha-antagonists' OR (adrenergic AND 'alpha antagonists') OR 'alfuzosin'/exp OR alfuzosin OR 'silodosin'/exp OR silodosin OR 'tamsu- losin'/exp OR tamsulosin) AND ('ejaculation'/exp OR ejaculation OR 'erectile dysfunction'/exp OR 'erectile dys- function' OR (erectile AND dysfunction)) AND [random- ized controlled trial]/lim}. Relevant data were also hand searched by browsing vari- ous sources (e.g., reference lists from reviews and study reports, congress abstracts, clinical trial registers such as www.clinicaltrials.gov, www.clinicaltrialsregister.eu, etc.). Title and abstract screening to exclude documents that did not meet the inclusion criteria was performed independ- ently by two authors. Duplicate references were deleted. Controversies were resolved by a third researcher. Full texts were downloaded to confirm or reject inclusion and to extract relevant information. Data extraction was conducted by two authors using a standardized form. The following information was obtained from each study: authors, publication year, study design, population, intervention, effect on sexual function (erectile, ejaculato- ry). In case of missing or insufficient information, we ana- lyzed the impact of missing data on the meta-analysis results and evaluated the potential risk of bias. Two authors independently performed the quality assess- ment by identifying potential biases using the Risk of Bias (ROB)-2 assessment tool of the Cochrane Collaboration (9). Study quality was evaluated based on pre-defined cri- teria in relation to randomization process (D1), deviations from the intended interventions (D1), missing outcome data (D3), measurement of the outcome (D4) and selec- tion of the reported result (D5). For each ROB domain, an evaluation was given, based on a specific algorithm, result- ing in the following rating: low risk, some concern, high risk. Disagreements were resolved by discussion. The presence of risk of bias did not influence the decision to include/exclude a study from quantitative analysis. Statistical analysis Statistical analysis was performed using the RevMan5 software. Dichotomous data (presence/absence of sexual dysfunction) and number of per-protocol or intent-to- treat patients were extracted to calculate odds ratios (OR), 95% confidence intervals (CI) to odds-ratios, and Z statis- tics (Random-effects model, Mantel-Haenszel method). Study heterogeneity was assessed by calculating I^2 (and 95% CI), which was interpreted as of lesser impor- tance (I^2 ≤ 40%), moderate (I^2 = 30%-60%), substan- tial (I^2 = 50%-90%) or considerable (I^2 ≥ 75%), according to Cochrane criteria. Funnel plots were drawn and visually evaluated to detect publication bias and small study effects. If publication bias was suspected, the Egger’s and Begg’s tests were imple- mented to assess funnel plot symmetry or asymmetry. Asymmetry tests were performed using the MetaEssentials- 1 software (Rotterdam School of Management, Erasmus University, The Netherlands). The ‘trim and fill’ missing study imputation approach was applied to funnel plots; if Archivio Italiano di Urologia e Andrologia 2022; 94, 2 R. Bapir, K. Hassan Bhatti, A, Eliwa, et al. 254 missing studies were imputed by this procedure, adjusted overall effect sizes (odds ratios) were calculated. RESULTS A PRISMA flow diagram illustrates the results of study selection process (Figure 1). We retrieved 612 records (Pubmed, 152; EMBASE, 456; other sources, 4). After title and abstract screening, we selected 125 articles by title and abstract screening (PubMed = 45 papers, EMBASE = 80). Following removal of 23 duplicates, the full text of the remaining 102 articles were examined. Twenty-seven arti- cles were excluded (2 because alpha-blockers were expressly used to treat premature ejaculation or as male oral contraceptives, 6 open-label studies, 5 non-controlled studies, 4 studies not reported in English, 3 reviews, 4 short term experimental studies in healthy subjects, 3 stud- ies not reporting sexual function outcomes). The remaining 75 papers were included in three analyses: alpha-blockers versus placebo (N=36) (10-45), compari- son of different alpha-blockers (N=31) (46-76) and com- parison of alpha-blockers administered at different dosages (N=8) (77-84) (Supplementary Materials - PICO Tables). Risk of bias Among the 75 studies included in qualitative analysis, the method of randomization was deemed to be at low risk of bias in 46 cases, and to unclear risk in 29. The risk of deviation from the intended intervention was rated as low in 62 studies, unclear in 12 and high in one. The ROB associated to missing outcome data was consid- ered to be low in 63 studies and unclear in 12. The risk of bias in measurement of outcome was considered to be low in 70 studies and unclear in 5. The risk of bias gen- erated by selection of the reported results was rated as low in 73 studies and as unclear in 2. In total risk of bias was considered low in 37 studies, unclear in 35 and high in 3 (Supplementary Materials - Risk of Bias). Analysis of funnel plots symmetry by Egger’s and Begg’s tests, and adjusted odds ratios when missing studies were imputed by the trim-and-fill procedure are shown in the (Supplementary Materials - Funnel plots & Symmetry tests). Significant asymmetry was detected by at least one test for any kind of alpha blockers (uroselective, non- uroselective or both) compared to placebo in BPH patients (endpoint: ejaculation), in the alpha blockers vs. standard care comparison in stone patients (endpoint: ejaculation), and in the alpha blockers vs. standard care or placebo comparison in stone patients (endpoint: ejac- ulation). Imputation of missing studies by the trim-and- fill procedure was implemented in 4 comparisons. In 3 cases, the significance or non-significance of adjusted odds ratios was not modified by imputation. Conversely, the adjusted odds ratio for ejaculatory disorders in stone patients treated with alpha adrenocep- tor blockers compared to placebo lost statistical significance. Alpha-blockers versus placebo A total of 36 studies were included in this analysis: 15 studies evaluat- ed ejaculatory disorders secondary to treatment with alpha-blockers compared to placebo (9 in patients with BPH, 1 in patients with CP/CPPS, 5 in patients with ureter- al stones) (10-24). In 7 studies ejaculatory disorders were com- pared in patients on treatment with alpha-blockers compared with standard conservative treat- ment of ureteral stones (25-31). In 9 studies, both ejaculatory and erectile dysfunction after treatment with alpha-blockers were com- pared to placebo in patients with BPH (32-40). Finally, 5 studies reported the effect on erectile function of alpha- blockers compared to placebo in BPH patients (41-45). Endpoint: ejaculatory disorders Compared to placebo, alpha-block- ers were associated with significant- ly increased odds of ejaculatory dis- orders in patients with LUTS associ- ated to BPH (OR: 7.53, 95% CI: 3.77 to 15.02, 23 series from 19 Figure 1. Flow chart. 255Archivio Italiano di Urologia e Andrologia 2022; 94, 2 Sexual function and alpha-blockers studies, 13006 participants, Z = 5.73, p < 0.00001, I2 = 55%) (Figure 2). Similarly, in patients with ureteral stones, patients taking alpha-blockers showed significantly higher odds for ejacu- latory disorders, compared to patients receiving placebo or standard care (OR: 2.86, 95% CI: 1.50 to 5.44, 12 series from 12 studies, 3192 participants, Z = 3.19, p < 0.001, I2 = 31%) (Figure 3). Significantly higher odds for ejaculatory disorders were confirmed in patients with ureteral stones taking alpha- blockers compared to patients either on placebo or on standard treatment (Forest plots shown in Supplementary Materials - Forest plots Figures 1-2). Compared to place- bo, uroselective alpha-blockers showed significantly high- er odds of ejaculatory disorders (OR: 11.46, 95% CI: 5.58 to 23.54, 16 series from 13 studies, 8580 participants, Z = 6.64, p < 0.00001, I2 = 49% (Figure 4), whereas non- selective alpha-blockers were not associated with higher Figure 2. Odds for ejaculatory disorders in patients with LUTS associated to BPH taking alpha-blockers. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with alpha adrenoceptor blockers (both uroselective and non-uroselective), compared to placebo. Figure 3. Odds for ejaculatory disorders in patients with ureteral stones taking alpha-blockers for medical expulsive treatment. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with alpha adrenoceptor blockers compared to placebo or standard treatment. Archivio Italiano di Urologia e Andrologia 2022; 94, 2 R. Bapir, K. Hassan Bhatti, A, Eliwa, et al. 256 odds of ejaculatory dysfunction (OR: 2.22, 95% CI: 0.72 to 6.84, 7 series, 4426 participants, Z = 1.38, p = 0.17, I2 = 12%) (Figure 5). Endpoint: erectile dysfunction The presence of erectile dysfunction in patients treated with alpha-blockers was investigated in 14 studies. Eleven studies (12 series) reported the rates of erectile dysfunction in patients on treatment with alpha-blockers (any kind) in comparison with placebo (32-39, 43-45). There was no statistically significant difference between the odds of erectile dysfunction assessed in the alpha- blocker treatment arm compared to placebo (OR: 0.88, 95% CI: 0.42 to 1.82, 12 series, 6631 participants, Z = 0.35, p = 0.73, I2 = 36%) (Figure 6). The lack of a sig- nificant inter-arm difference versus placebo was con- firmed when uroselective and non-selective alpha-block- ers were analyzed separately (Forest plots shown in Supplementary Materials - Forest plots Figures 3, 4). In three of the above reported studies, erectile function alterations were also evaluated by administering ques- tionnaires to enrolled patients. Hofner et al. (33) evaluat- ed the effect of alpha-blockers on sexual function by administering a quality-of-life assessment questionnaire including three questions on sexual function (interest in sex, erection, ejaculation). The authors reported the over- all evaluation of sexual function without showing the results of the three separate domains. A trend to improve- ment of the overall sexual function was observed after tamsulosin (p = 0.042), whereas no differences were observed when tamsulosin was compared to alfuzosin. Rosen et al. (39) reported changes of the DAN-PSSsex score after alfuzosin treatment. The DAN-PSSsex tool includes questions on erectile and ejaculatory function, and on bother associated with these two functions. Alfuzosin treatment was associated with a significant improvement of erectile function compared with placebo (p = 0.02), whereas treatment didn’t appear to influence the ejaculatory function. Shelbaia et al. (44) observed that the use of tamsulosin was associated with increased IIEF scores (p = 0.047) in patients with LUTS and erectile dys- function. Three additional studies were not included in our quantitative analysis. One study evaluated the effects of the oral administration of the nonselective alpha- Figure 4. Odds for ejaculatory disorders in patients in patients with LUTS associated to BPH taking uroselective alpha-blockers. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with uroselective alpha adrenoceptor blockers compared to placebo. Figure 5. Odds for ejaculatory disorders in patients in patients with LUTS associated to BPH taking non-uroselective alpha-blockers. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with non-uroselective alpha adrenoceptor blockers compared to placebo. 257Archivio Italiano di Urologia e Andrologia 2022; 94, 2 Sexual function and alpha-blockers adrenergic antagonist phentolamine in patients with erec- tile dysfunction. Full erection was achieved after on- demand administration of phentolamine at different doses (from 20 to 60 mg) more frequently than after placebo. However, the sample size was too small for sta- tistical analysis (41). Another study evaluated the effect of a single dose of the selective, orally-active alpha1-A- adrenoceptor antagonist Ro70-0004 on the erectile func- tion in a group of men with erectile dysfunction. Ro70- 0004 did not improve the erectile function when com- pared to placebo (42). Finally, in patients with painful ejaculation, Safarinejad et al. (40) found that the inter- course satisfaction domain IIEF scores were not signifi- cantly improved after tamsulosin (p = 0.08). Other endpoints Few studies reported about the alterations of sexual desire after administration of alpha-blockers. No significant dif- ferences of desire after alfuzosin or tamsulosin and place- bo were reported. Kirby et al. (34) reported similar decreases of libido after alfuzosin or placebo (-3.6% vs - 1.9%, P = 0.58). Van Kerrebroeck et al. (45) reported no cases of decreased desire after alfuzosin 10 mg/day, 0.7% cases after alfuzosin 2.5 mg t.i.d. and 0.7% cases after placebo. Hofner et al. (33) reported no differences between tamsulosin and placebo (0.8% vs 0%, p = 0.306) and Singh et al. (19) no cases of decreased desire after both tamsu- losin or placebo. Hofner et al. (33) found no cases of decreased libido after tamsulosin or alfuzosin. Comparisons between alpha-blockers A total of 31 studies compared the effect of different alpha-blockers on sexual function (46-76). Out of 31 tri- als, 15 compared the risk of ejaculatory disorders after Figure 7. Odds for ejaculatory disorders in patients taking silodosin or tamsulosin. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with silodosin. Figure 6. Odds for erectile dysfunction in BPH patients taking alpha-blockers. Data to the left of the vertical no-effect axis indicate lower odds for erectile dysfunction in patients treated with placebo compared to alpha adrenoceptor blockers. Archivio Italiano di Urologia e Andrologia 2022; 94, 2 R. Bapir, K. Hassan Bhatti, A, Eliwa, et al. 258 tamsulosin compared with silodosin (49-54, 60, 62, 64, 65, 70, 71, 73-75), 5 studies evaluated the effect of nafto- pidil compared with a uroselective alpha-blocker on ejac- ulation (including a study comparing naftopidil with both tamsulosin and silodosin) (59, 61, 68, 72, 73), 7 studies compared alfuzosin with uroselective alpha- blockers (46-48, 55-57, 60), 4 studies compared tera- zosin or doxazosin with tamsulosin (58, 63, 66, 76) and one study terazosin with doxazosin (67). Silodosin was associated with significantly increased odds of ejaculatory dysfunction compared with tamsulosin (OR: 3.52, 95% CI: 2.18 to 5.68, 15 series, 1512 partici- pants, Z = 5.15, p < 0.00001, I2 = 0%) (Figure 7). Naftopidil showed significantly lower odds of ejaculatory dysfunction compared to uroselective alpha-blockers (OR: 0.29, 95% CI: 0.13 to 0.64, 6 series from 5 studies, 474 participants, Z = 3.04, p = 0.002, I2 = 0%) (Figure 8). Alfuzosin was associated with significantly lower odds of ejaculatory disorders compared to uroselective alpha- blockers (OR: 0.17, 95% CI: 0.07 to 0.38, 8 series from 7 studies, 877 participants, Z = 4.27, p < 0.0001, I2 = 0%) (Figure 9). Summary of findings Summary of finding (SOF) tables, containing illustrative comparative risks (assumed control risks and correspon- ding intervention risks) and odds ratios relative to each single meta-analysis are presented as Supplementary Materials. SOF tables also contain evaluations of the quality of the evidence relative to each meta-analysis, rated according to GRADE criteria. Single studies not included in quantitative analysis Zaytoun et al. (2/50 vs 0/50) (76), Pompeo et al. (4/83 vs 2/82) (66) and Kirby et al. (2/50 vs 0/48) (58) observed more frequently ejaculatory disorders after tamsulosin compared to doxazosin. Narayan et al. (63) described higher rates of ejaculatory dysfunction after tamsulosin compared to terazosin [37/1002 (3.7%) vs 3/981 (0.3%)]. Samli et al. (67) observed similar rates of erectile dysfunc- tion after doxazosin versus terazosin (0/25 vs 1/25). Comparison between different dosages of alpha-blockers We retrieved 8 studies (77-84) designed to compare the clinical efficacy and tolerability of different alpha-block- ers administered at different doses and time intervals. The designs of the studies were too heterogenous for quantitative analysis. No differences in the rate of ejaculatory disorders were observed with different formulations and different doses Figure 8. Odds for ejaculatory disorders in patients taking naftopidil or uroselective alpha-blockers. Data to the left of the vertical no-effect axis indicate lower odds for ejaculatory disorders in patients treated with naftopidil compared to uroselective alpha adrenoceptor blockers. Figure 9. Odds for ejaculatory disorders in patients taking alfuzosin compared to uroselective alpha-blockers. Data to the left of the vertical no-effect axis indicate lower odds for ejaculatory disorders in patients treated with alfuzosin. 259Archivio Italiano di Urologia e Andrologia 2022; 94, 2 Sexual function and alpha-blockers of doxazosin (4 mg vs 8 mg) (77, 78). The improvement in IIEF scores after extended-release doxazosin (4 or 8 mg once daily) was similar to the one observed after fast- release doxazosin (1-8 mg once daily) (78). Similarly, the administration of tamsulosin at different doses resulted in similar effects on ejaculatory function (81-83). Rates of ejaculatory disorders were not different after tamsulosin 0.4 mg versus 0.2 mg (81, 82), or 0.4 mg once daily every other day (83). The timing of administration of silodosin appears to change the effects of the drug on sexual function. Silodosin 4 mg twice-daily induced a higher rate of ejacu- latory disorders compared to silodosin 4 mg taken once a day (10/115 vs 67/115) or silodosin 8 mg administered after breakfast (46/208 vs 32/212) (79, 80). DISCUSSION Alpha-1 adrenoceptor blockers have been shown to be very effective in counteracting lower urinary tract symp- toms associated with benign prostatic hyperplasia (85, 86), as well as in facilitating the spontaneous passage of stones from the distal ureter (87, 88). However, this class of drugs can lead to cardiovascular side effects and sexu- al dysfunction, thus potentially worsening the quality of life of patients and possibly causing a reduction in the compliance to long-term treatment. Since alpha-adrener- gic receptors are highly expressed in male genital organs, adrenergic blockade can potentially affect erection, ejacu- lation, and sexual desire. Ejaculation The influence of alpha-blockers on ejaculation is well known, although the underlying physiological mecha- nism for such effect is not yet well defined. Our analysis confirms that the odds for ejaculation disorders are greater in patients taking alpha-blockers of any kind, compared to placebo. Moreover, when the effects of dif- ferent alpha-blocking agents are analyzed separately, the odds for abnormal ejaculation are greater upon adminis- tration of uroselective alpha blockers (tamsulosin and silodosin). Conversely, comparison between alfuzosin and placebo does not result in statistically significant results. The comparison between different alpha-blocking agents showed that silodosin and tamsulosin were more frequently associated with ejaculation disorders when compared to non-selective alpha-blockers. Tamsulosin and, to a greater extent, silodosin, show super-selective binding with the alpha1A receptor, while alfuzosin, doxazosin and terazosin show comparable affinity with the three subtypes of alpha1-adrenergic receptors. Naftopidil on the other hand exhibits a unique selectivity for alpha1B receptors. The different binding affinity (or selectivity) for alpha1-adrenergic receptor subtypes explains the different effects of alpha-blockers on ejaculation. Ejaculatory disorders associated with administration of alpha-1 blockers were initially thought to be a consequence of bladder neck relaxation, causing in turn retrograde ejaculation. Further studies clarified the mechanisms whereby ejaculation disorders occur fol- lowing the use of uroselective alpha-blockers. Disorders of ejaculation after tamsulosin and silodosin have been related to both a peripheral effect on the vas deferens and/or seminal vesicles and a central effect in the coordi- nation of ejaculation (89). At the peripheral level, ejacu- lation disorders have been related to the decreased capac- ity of contraction of the seminal vesicles and of the vas deferens. This is supported by the evidence that alpha-1A adrenoceptor subtype mRNA is predominant in human seminal vesicles, and that spermatic cells are not detected in the urine after ejaculation following silodosin adminis- tration. This shows that ejaculatory dysfunction caused by silodosin is not related to retrograde ejaculation but rather to a loss of seminal emission (90, 91). Similarly, administration of 0.8 mg tamsulosin to healthy volun- teers resulted in reduction of the ejaculatory volume in almost all subjects, without causing a significant differ- ence in post-ejaculation urinary sperm concentrations when compared to placebo or alfuzosin (92). Unlike other alpha1-blockers, tamsulosin can cross the blood- brain barrier and bind to dopaminergic and/or serotoner- gic receptors that are involved in the central coordination of ejaculation (93). A strong affinity of alpha1-adreno- ceptor antagonists for D2- and 5HT1A-like receptors for has been demonstrated, suggesting that these drugs may act as antagonists of dopaminergic receptors mediating the contraction of the vas deferens (94). Erection There are conflicting data about the effect of alpha-block- ers on erection, mainly because the erectile function is the result of a complex interplay between multiple biochem- ical signals responding to several neurotransmitters and vasoactive agents. Basically, penile tumescence is associ- ated with relaxation of the erectile tissue whereas detumescence is caused by contraction of the erectile tis- sue. Postsynaptic alpha1-adrenoceptor activation causes the contraction of the erectile tissue, leading to penile flaccidity and detumescence. For this reason, alpha- adrenoceptor antagonists can promote the relaxation of the muscles of the trabeculae of the corpora cavernosa and induce erection, as demonstrated by erection induced by intra-cavernous injection of alpha-adrenocep- tor antagonists (95, 96). In addition, alpha-blocker-induced priapism is a rare but well documented side effect of treatment (97). At the systemic level, blockage of adrenergic receptors has a more complex effect on the regulation of erectile function because it can occur at both peripheral and cen- tral levels (through ascending pathways to the brain and descending pathways to the spinal cord) and involve var- ious alpha1- or alpha2-adrenoceptor subtypes. The effect of each drug will depend on the central and peripheral effects exerted on the different receptors, causing in turn specific effects on erectile function (98). Finally, hemo- dynamic effects of non-selective alpha-blockers may harm erectile function because of symptomatic hypoten- sion side effects (99). Our meta-analysis demonstrated neither greater odds of erectile dysfunction or impotence upon exposure to alpha-blockers, nor differences of odds of erectile dys- function evoked by treatment with uroselective or non- selective alpha-blockers compared to placebo. Thus, the potential effect of alpha-blockers on erectile Archivio Italiano di Urologia e Andrologia 2022; 94, 2 R. Bapir, K. Hassan Bhatti, A, Eliwa, et al. 260 function therefore remains unknown. In our analysis we excluded studies that evaluated the effects of combination therapy with alpha-1 adrenergic antagonists and phospho- diesterase-5 (PDE5) inhibitors on sexual function. Interestingly, some studies have shown an additive favor- able effect of the combined use of alpha-blockers and PDE5 inhibitors on erectile dysfunction (100). In 2014, a meta-analysis demonstrated that alpha-blockers may enhance the efficacy of PDE5 inhibitors on erectile dysfunction in men with LUTS suggestive of BPH (101). However, a more recent review found no significant differ- ence of the mean change of IIEF between combination therapy and PDE5 inhibitors-monotherapy concluding that benefits regarding the treatment of ED are not clear (102). Limitations A limitation of this meta-analysis is the disparity of assess- ment criteria and definitions used to describe sexual dys- function associated with alpha-blockers. Ejaculation disorders have been defined indifferently as abnormal ejaculation, ejaculatory disorders, decreased ejaculatory volume, anejaculation, and retrograde ejacu- lation. Some of these terms are generic, others imply spe- cific pathophysiological alterations that may not corre- spond to clinically observable manifestations. The presence of retrograde ejaculation has been ques- tioned by recent studies which have shown that the ejac- ulatory alterations caused by alpha-blockers are due to a lack of semen emission, that should be better defined as anejaculation. The different physiological mechanisms that are at the origin of failure of semen emission, or of retrograde ejaculation, can be associated with different orgasmic dysfunctions. On the other hand, ejaculation disorders have rarely been evaluated with specific ques- tionnaires such as DAN-PSS or MSQH. Erectile dysfunction was also not uniquely defined in the different studies that used both the term impotence and erectile dysfunction, with only a few studies assessing the latter with the IIEF questionnaire. In order to take into account the diversity of diagnostic methods and tools used to ascertain ejaculatory or erec- tile dysfunction in included studies, we have used in all metanalyses a random-effect model (103). 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Common methodological issues in systematic reviews of effectiveness. Int J Evid Based Healthc. 2015; 13:196-207. Correspondence Rawa Bapir Dr.rawa@yahoo.com Smart Health Tower, Sulaymaniyah, Kurdistan region, Iraq Kamran Hassan Bhatti kamibhatti92@gmail.com Urology Department, HMC, Hamad Medical Corporation, Qatar. Ahmed Eliwa ahmedeliwafarag@gmail.com Department of Urology, Zagazig University, Zagazig, Sharkia, Egypt. Herney Andrés García-Perdomo herney.garcia@correounivalle.edu.co Universidad del Valle, Cali, Colombia Nazim Gherabi, MD ngherabi@gmail.com Faculty of Medicine Algiers 1, Algiers, Algeria Derek Hennessey, MD derek.hennessey@gmail.com Department of Urology, Mercy University Hospital, Cork, Ireland Vittorio Magri, MD vittorio.magri@virgilio.it ASST Nord Milano, Milan, Italy Panagiotis Mourmouris, MD thodoros13@yahoo.com 2nd Department of Urology, National and Kapodistrian University of Athens, Sismanoglio Hospital, Athens, Greece Adama Ouattara, MD adamsouat1@hotmail.com Division of Urology, Souro Sanou University Teaching Hospital, Bobo-Dioulasso, Burkina Faso Gianpaolo Perletti gianpaolo.perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy Joseph Philipraj, MD josephphilipraj@gmail.com Department of Urology, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India. Alberto Trinchieri, MD (Corresponding Author) alberto.trinchieri@gmail.com Urology School, University of Milan, Milan (Italy) Noor Buchholz noor.buchholz@gmail.com Sobeh's Vascular and Medical Center, Dubai Health Care City, Dubai, United Arab Emirates