Effects of α 1 -Adrenoceptor Antagonists on Male Sexual Function

Transcription

1 Drugs 2006; 66 (3): LEADING ARTICLE /06/ /$44.95/ Adis Data Information BV. All rights reserved. Effects of α 1 -Adrenoceptor Antagonists on Male Sexual Function Marleen M. van Dijk, 1 Jean J.M.C.H. de la Rosette 1 and Martin C. Michel 2 1 Department of Urology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 2 Department of Pharmacology and Pharmacotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Abstract α1-adrenoceptor antagonists such as alfuzosin, doxazosin, tamsulosin and terazosin are first-line agents for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH), but are only second-line agents (doxazosin and terazosin only) for the treatment of arterial hypertension. Sexual function is complex and includes multiple domains such as sexual desire (libido), erectile function and ejaculatory function. Erectile and ejaculatory functions are frequently reduced in patients with BPH and can impact on their quality of life. Therefore, the treatment of BPH should aim to maintain or even restore sexual function. α1-adrenoceptor antagonists lack major effects on sexual desire in placebo-controlled studies. Reports on erectile function are inconsistent, with both beneficial and adverse effects being reported, but impotence can occur in some patients without clear differences between drugs. Ejaculatory dysfunction during treatment may represent (relative) anejaculation. It occurs more frequently with tamsulosin than with other drugs of this class, but the differences are not big enough to be consistently detectable in directly comparative studies. We propose that such differences between drugs should be weighed against differences in cardiovascular tolerability when choosing the optimal treatment for each patient. α1-adreoceptor antagonists (α-blockers) such as doxazosin, prazosin or terazosin were originally in- troduced for the treatment of arterial hypertension but, following publication of the ALLHAT (An- tihypertensive and Lipid-Lowering treatment to pre- vent Heart Attack Trial) study, [1] are no longer considered-first line drugs in this indication. [2] However, α-blockers are also used in the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH), where they have become the most widely used form of rational treatment. Alfuzosin and tamsulosin are α-blockers which are only used in the treatment of BPH but not of hypertension. Both hypertension and BPH are frequently associated with disturbances of sexual function. [3-6] Therefore, any treatment of hypertension and BPH should strive to improve, or at least maintain, sexual function in these patients. Sexual function is complex and consists of multi- ple domains including sexual desire (libido), erectile function and ejaculatory function. Epidemiological studies among elderly men demonstrate that erectile and ejaculatory functions are the most frequently disturbed domains of sexual function. While dis-

2 288 van Dijk et al. turbed ejaculatory function was reported to be associated with an adverse impact on sexual activity in patients who had undergone surgical or minimally invasive BPH treatment, [7] other studies report that it is considerably less bothersome to patients than erectile dysfunction. [8,9] Painful ejaculation occurs much less frequently in elderly men, but appears to be the most bothersome form of sexual dysfunction. [9] The present overview first considers methodological issues in the analysis of adverse effects on sexual function associated with the use of α-blockers, and then summarises the effects of individual α-blockers. Our data are based on a systematic review of the published literature (MEDLINE search ending in June 2005 and a manual search of the abstracts of the European and American urological congresses of ) as well as the regulatory information on the individual drugs. Since al- fuzosin, doxazosin, tamsulosin and terazosin represent the vast majority of the published data on sexual adverse effects of α-blockers, our manuscript focuses mainly on these four drugs. It should be noted that almost all reported findings with regard to sexual adverse effects of α-blockers come from the BPH studies, with only limited information being available in the hypertensive populations. 1. Methodological Considerations An unbiased evaluation of the frequency and severity of sexual adverse effects of α-blockers faces several methodological challenges. Firstly, many studies on the use of α-blockers have not specifically reported on the occurrence of sexual adverse effects. While this can be considered as evidence that such adverse events did not occur frequently, it nevertheless creates a problem in the analysis of the overall occurrence of such events. Thus, in many studies, sexual adverse effects were reported because they exceeded a certain threshold. If studies with a lower incidence do not report specific numbers, the resulting mean involves a publication bias for higher numbers. Secondly, the published incidences come from different types of studies that involve intrinsic re- porting bias. Thus, randomised controlled trials (RCTs), in general, report higher incidences of any adverse event than open-label studies (OLS). While the former are more reliable to demonstrate differ- ences with a control group, the latter may be more representative for routine clinical practice. Similar- ly, studies performed in the US tend to report more adverse effects than those performed in Europe. Moreover, the total incidence of any adverse event increases with observation time, and hence the re- ported incidence of sexual adverse effects tends to be higher in the longer studies. Whereas some stud- ies have only investigated spontaneous reports of adverse events, others have systematically looked into this with specific questions that lead to higher reported incidences. All of these factors make inter- study comparisons between drugs difficult. Thirdly, some drugs have been tested in multiple dose strengths or in dose titration designs, and the corresponding publications did not always discrimi- nate at which dose level a given adverse event has occurred. In this regard, Asian studies tend to have used lower doses than US studies, with European studies being intermediate. Fourthly, multiple formulations have been used for some drugs. For example, alfuzosin was origi- nally introduced in a standard formulation (recommended dose 2.5mg thrice daily), thereafter in a sustained-release (SR) formulation (recommended dose 5mg twice daily), and finally in an extendedrelease (XL) formulation (recommended dose 10mg once daily). Doxazosin was originally marketed in a standard formulation, but later a gastrointestinal therapeutic system (GITS) formulation was intro- duced (recommended dose in both cases 4 8mg once daily). Tamsulosin was originally marketed in a modified-release (MR) formulation, but recently an oral controlled absorption system (OCAS) for- mulation was introduced (recommended dose in both cases 0.4mg once daily). Finally, the reporting standards have been hetero- geneous with regard to the classification of sexual adverse effects as well as to publication strategies. Thus, in some cases, pooled analyses of multiple studies have been published, where not all underly-

3 Effects of α1-adrenoceptor Antagonists on Male Sexual Function 289 Table I. Effects of α 1-adrenoceptor antagonists on sexual desire Study type No. of pts Decrease in sexual desire (% pts) Description a Reference active comparator active comparator treatment treatment Alfuzosin RCT mg, 12wk 11 RCT mg XL, 12wk 11 RCT mg SR, 6mo, comparator was finasteride 12 (5mg) Doxazosin RCT mg dose titration, 1y 13 RCT mg dose titration, 4.5y. The numbers 14 shown are the rates per 100 person-years of follow-up Tamsulosin RCT mg MR, pooled analysis of three 12wk 16 European phase III studies including [15] RCT mg MR, 1y, comparator was Permixon 17 (320mg) OLS mg MR, up to 4y open-label extension 20 of [15,18,19] OLS Pooled data for mg MR, open-label 23 extension of [21,22] for up to 2y Terazosin RCT mg dose titration, 1y 24 a Drug doses refer to the immediate-release formulation of a drug, and comparator refers to placebo, unless otherwise noted. MR = modified-release formulation; OLS = open-label study; pts = patients; RCT = randomised controlled trial; SR = sustained-release formulation; XL = extended-release formulation. ing studies have been reported separately; in those function. However, at least one RCT each has been cases, we have used the data from the pooled analy- reported for alfuzosin, doxazosin, tamsulosin and sis only. In other cases, it appears that data from a terazosin in the BPH population (table I). On the single study have been published as part of multiple basis of these data, it appears that adverse effects on manuscripts; in those cases, we have attempted to sexual desire occur similarly rarely, i.e. in about 1% quote the most comprehensive report only. of patients, in α-blocker- and placebo-treated pa- From these considerations, it becomes clear that tients. Results from OLS are largely in line with comparisons between dose levels and formulations those from the RCT. of a given drug are difficult. Similarly, comparisons The US package insert for alfuzosin XL makes between drugs, particularly when based on indirect no statements on libido. [25] The US package insert comparison of studies involving only a single drug, for doxazosin in the treatment of BPH reports deshould be approached with caution. creased libido in 0.8% and 0.3% of patients treated 2. Sexual Desire with doxazosin and placebo, respectively, but provides no such data for its use in the treatment of Sexual desire is a complex function of the central hypertension. [26] The US package insert for tamnervous system but the underlying mechanisms sulosin reports decreased libido in 1.0%, 2.0% and have not been defined in detail. [10] The effects of α- 1.2% of patients treated with tamsulosin MR 0.4mg, blockers on sexual desire have been reported less 0.8mg and placebo, respectively. [27] The US pack- frequently than those on other domains of sexual age insert for terazosin reports decreased libido in

4 290 van Dijk et al. 0.6% and 0.2% of hypertension patients treated with may also cause pro-erectile effects as a result of a terazosin and placebo, respectively, but provides no central nervous mechanism. [41,42] On the other hand, such data for its use in BPH. [28] Thus, α-blockers as blood pressure lowering is a class effect of α-blocka class do not appear to have major adverse effects ers (although it may not occur to a clinically relevant on sexual desire. In the absence of directly compara- extent with tamsulosin), and this can be associated tive studies, there is no evidence of differential with adverse effects on erectile function. [43] Thereeffects of any member of this group. fore, the net effect of an α-blocker on erectile function is likely to depend on the balance between proerectile 3. Erectile Function effects in the brain and penis and anti- erectile effects as a result of blood pressure lower- The physiology of erectile function involves cen- ing, and perhaps other mechanisms. This balance tral and peripheral mechanisms. [29] The human penis needs to be assessed individually in clinical studies expresses all three subtypes of α1-adrenoceptors, for each α-blocker. with α1a- and α1b-adrenoceptors being most and Most clinical studies with α-blockers have, if least abundant at the mrna level, respectively. [30-32] anything, reported adverse rather than beneficial Human penile α1-adrenoceptors have been demoneffects on erectile function (table II). Such adverse strated at the protein level in radioligand binding effects were typically classified as impotence studies and appear to belong to the α1a- and α1bwithout further clarification as to whether this spesubtype, whereas α1d-adrenoceptors have not been cifically represents erectile dysfunction; therefore, detected at the protein level. [30,33-35] Stimulation of the term impotence is also used here. Alfuzosin human penile α1-adrenoceptors promotes smooth treatment was associated with a greater incidence of muscle contraction and hence detumescence. [33,36] impotence than placebo in three RCTs (two of these This is the pharmacological basis for the use of the with the 10mg XL formulation), with a smaller α1-agonist phenylephrine in the treatment of priapincidence in one study and a roughly similar inciism. Therefore, it appears logical that an α-blocker, dence in four studies. However, the incidence of acting locally in the penis, could have pro-erectile alfuzosin-associated impotence did not exceed 1.5% effects. Indeed, oral administration of the mixed α1/ in most RCTs and was very low (one of 2767 α2-adrenoceptor antagonist phentolamine has some patients) in an OLS. efficacy in patients with erectile dysfunction compared with placebo. [37] Similarly, addition of doxtreatment The incidence of impotence during doxazosin azosin to an intracavernosal administration of alone of BPH was greater than with placebo in prostadil, [38] or to an existing treatment with RCT of 1-year duration but similar to that with sildenafil in previous non-responders to sildenafil placebo in two RCTs, one being a 4-year study with monotherapy, significantly improved erection. [39] >700 patients per treatment arm (table II). A 4-year The pro-erectile effects of the antidepressant RCT with doxazosin in the treatment of hypertentrazodone have also been linked to its α1-adreproblems sion has reported numerically smaller incidences for noceptor antagonism. [34] However, the α1a-selection with obtaining and maintaining an erec- tive antagonist RO has been tested clinically than with placebo, but the differences failed to for the treatment of erectile dysfunction, but at a reach statistical significance. Within the same study, dose of 5mg did not cause improvement relative to other antihypertensive medications had numerically placebo. [40] Taken together, these data demonstrate higher incidences, in some cases reaching statistical that α-blockers, most probably acting locally on significance. [60] In an RCT comparing the standard receptors in the penis, have a pro-erectile potential, and GITS formulation of doxazosin (not involving a but that their effects may not always be strong placebo group), a statistically significant worsening enough to be used in the treatment of erectile dysfunction. of erectile function relative to baseline was reported Animal studies suggest that α-blockers with the standard but not the GITS formulation;

5 Table II. Effects of α1-adrenoceptor antagonists on erectile function Study type No. of patients Decrease in erectile function (% patients) Description a Reference active treatment comparator active treatment comparator Alfuzosin RCT < mg, 6mo 44 RCT mg, 12wk 11 RCT mg SR, 1 and 3mo, pooled data from two studies 45 RCT mg XL, 12wk 11 RCT mg XL, 12wk 46 RCT mg XL, 12wk 46 RCT mg XL, 12wk 47 RCT mg XL, 12wk 47 RCT mg, 12wk, comparator was tamsulosin (0.4mg MR) 19 RCT mg SR, 6mo, comparator was finasteride (5mg) 12 RCT mg dose titration, 14wk, comparator was 48 doxazosin (1 8mg dose titration) OLS 3095 < mg, 2mo, impotence in one patient 49 OLS mg XL, 1y 50 Doxazosin RCT mg dose-titration, 14wk 51 RCT mg, 12wk 52 RCT mg, 12wk 52 RCT mg dose titration, 1y 13 RCT mg dose-titration, 4.5y, the numbers shown are the 14 rates per 100 person-years of follow-up RCT mg dose titration, 14wk, comparator was alfuzosin 48 ( mg dose titration) OLS mg dose titration, 6mo extension of earlier 53 unspecified RCT Tamsulosin RCT mg MR, pooled analysis of three 12wk European 16 phase III studies including [15] RCT mg MR, 12wk 47 RCT mg MR, 12wk, comparator was alfuzosin (3 x mg) RCT mg MR, 1y, comparator was finasteride (5mg) 54 OLS mg MR, 6mo 55 OLS mg MR, up to 4y open-label extension of [15,18,19] 20 Continued next page Effects of α1-adrenoceptor Antagonists on Male Sexual Function 291

6 292 van Dijk et al. Table II. Contd Study type No. of patients Decrease in erectile function (% patients) Description a Reference active treatment comparator active treatment comparator OLS Pooled data for mg MR, open-label extension 23 of [21,22] for up to 2y Terazosin RCT mg dose titration, 1y 24 RCT mg dose titration, 2 6mo, pooled analysis of six 56 studies OLS mg dose titration, 2y 57 OLS mg dose titration, 6mo 58 OLS Maximum dose 40mg in 1 2 doses, 6mo in hypertensive 59 patients a Drug doses refer to the immediate-release formulation of a drug, comparator refers to placebo, and data are from benign prostatic hyperplasia patients unless otherwise noted. GITS = gastrointestinal therapeutic system formulation; MR = modified-release formulation; OLS = open-label study; RCT = randomised controlled trial; SR = sustained-release formulation; XL = extended-release formulation. absolute incidences were relatively high in both groups. [61] The incidence of impotence with tamsulosin was greater than with placebo in one RCT and similar to placebo in another RCT (table II). A report based on the British prescription event monitoring scheme described impotence as occurring in 2% of finasteride-treated patients but only in three of tamsulosin-treated BPH patients. [62] The incidence of impotence with terazosin was greater than with placebo in a pooled analysis of six RCTs and another long-term RCT in BPH patients (table II). Terazosin-associated erectile dysfunction was also reported in OLS in both BPH and hypertensive patients (table II). We have identified three directly comparative RCTs that report on impotence as an adverse event with alfuzosin as compared with other α-blockers. One study reported that impotence was similarly frequent with alfuzosin 2.5mg thrice daily as with tamsulosin MR 0.4mg once daily. [19] A later study with alfuzosin XL 10mg and 15mg also reported no statistically significant difference with tamsulosin MR, although the incidence with the latter was numerically higher. [47] On the other hand, another study reported that impotence was numerically more frequent with alfuzosin 5 10mg than with doxazosin 1 8mg. [48] Another randomised but openlabel comparative study on BPH treatment did not report the total incidence of impotence but stated that study discontinuation as a result of impotence occurred in 0.2% of patients with tamsulosin MR and in 0.3% of patients with terazosin. [63] The US package inserts list impotence as an adverse event to occur in >1% of patients and more often than with placebo for alfuzosin [25] and for terazosin [28] in the treatment of BPH, but not for doxazosin [26] in the treatment of BPH or hypertension, not for tamsulosin [27] in the treatment of BPH and not for terazosin in the treatment of hypertension. [28] While these inserts reflect the results of the studies for registration in the respective indications in the US, a balanced view of the data indicates that impotence is a rare event during α-blocker treatment and that there is no conclusive evidence that it

7 Effects of α1-adrenoceptor Antagonists on Male Sexual Function 293 occurs more frequently with one than with other reviewed literature, such data suggest that the undermembers of the group. Moreover, the package in- lying mechanism involves effects on the seminal serts for all four drugs describe priapism as a rare vesicles and/or vas deferens rather than on the bladbut possible adverse effect. [25-28] Given this complex der neck. These could occur locally, i.e. by direct situation, the prescribing physician can only be ad- drug effects on those tissues, or indirectly, e.g. by vised that both erectile dysfunction and, more rarely, effects on their central nervous regulation. Support priapism can occur during treatment with any α- for the latter possibility comes from a study in rats, blocker, and that the situation must be monitored which demonstrated that 8-hydroxy-2-(di-N-propyspecifically in any given patient. lamino)tetralin injections into the cerebral ventricles induce contractions of the bulbospongiosus muscle 4. Abnormal Ejaculation which were inhibited by intravenous administration of tamsulosin but not of comparative doses of al- It has long been assumed that α-blockers exert fuzosin. [68] While these data demonstrate central their beneficial effects in BPH patients by a relaxa- stimulation of bulbospongiosus muscle, they do not tion of smooth muscle in the prostate, urethra and allow conclusions regarding the site of action of bladder neck. [64] Such relaxation implies a reduced tamsulosin. Support for a peripheral effect comes resistance of the prostatic urethra and bladder neck from the clinical finding that α-blocker-associated for the ejaculate coming from the vas deferens. In abnormal ejaculation also exists in spinal cord injury analogy to the well established retrograde ejaculapatients. Irrespective of the anatomical location tion after transurethral resection of the prostate, [65] it of the receptors mediating abnormal ejaculation, its has therefore been assumed that abnormal ejaculapharmacological identity remains to be determined. tion with α-blockers represents retrograde ejacula- Hisasue et al. [66] have proposed an α1-adrenergic tion. However, this hypothesis has only been tested mechanism based on their finding that human semivery recently. A study with 17 Korean urologists as nal vesicles express α1-adrenoceptors at the mrna volunteers found that a 3-day treatment with tamlevel, with α1a-, α1b- and α1d-subtypes being presulosin MR 0.2 and 0.4mg once daily reduced the sent in a 75 : 12 : 13% ratio. On the other hand, mean ejaculatory volume by 45% and 49%, respectamsulosin is associated with the highest likelihood tively; however, no sperm was detectable in midof abnormal ejaculation (see below) but, as a result stream urine obtained after ejaculation. [66] In another of its subtype selectivity, if anything, occupies fewer study, 57 young, healthy volunteers (mean age 25 α1-adrenoceptors. Therefore, we propose that a reyears, primarily African Americans) were treated ceptor distinct from α1-adrenoceptors mediates abfor 5 days with either placebo, tamsulosin MR normal ejaculation. On the basis of the receptor 0.8mg once daily or alfuzosin XL 10mg once daily affinity profile of tamsulosin, [70] we consider a subin a randomised, double-blind, crossover manner. [67] Mean ejaculate volume decreased significantly relamost likely candidate but this needs to be tested type of serotonin or dopamine receptors to be the tive to baseline with tamsulosin ( 2.4mL) but not with placebo (+0.4mL) or alfuzosin (+0.3mL); 35% experimentally. of tamsulosin but 0% of placebo- or alfuzosin-treatgreater RCTs with alfuzosin have reported a numerically ed subjects reported total anejaculation. Neverthestudies incidence of abnormal ejaculation in two less, sperm was rarely detected in post-ejaculate (both performed with the 10mg XL dose) urine. Taken together, these two studies demonstrate compared with placebo, whereas no abnormal ejacu- that α-blocker-associated abnormal ejaculation may lation was seen with alfuzosin or placebo in two represent (relative) anejaculation rather than retro- other studies (table III). Abnormal ejaculation data grade ejaculation. with doxazosin have only been reported from one While a definitive assessment of this awaits pubtreatment RCT (a 4-year study with about 750 patients per lication of these studies as full reports in the peer- arm), where the incidence was similarly

8 Table III. Effects of α1-adrenoceptor antagonists on ejaculation Study type No. of patients Abnormal ejaculation (% patients) Description a Reference active treatment comparator active treatment comparator Alfuzosin RCT mg, 12wk 11 RCT mg XL, 12wk 11 RCT mg XL, 12wk 46 RCT mg XL, 12wk 46 RCT mg XL, 12wk 47 RCT mg XL 12wk 47 RCT mg, 12wk, comparator was tamsulosin 19 (1 0.4mg MR) RCT mg SR, 6mo, comparator was finasteride 12 (5mg), reported as ejaculation failure OLS mg SR, 2mo 49 OLS mg XL, 9mo extension of [11] 71 OLS mg XL, 1y 50 Doxazosin RCT mg dose titration, 1y 13 RCT mg dose titration, 4.5y. The numbers 14 shown are the rates per 100 person-years of follow-up RCT mg GITS dose titration, 8wk, comparator 72 was tamsulosin ( mg MR dose titration) Tamsulosin RCT mg MR, 4wk 73 RCT mg MR, 4wk 73 RCT mg MR, 4wk 73 RCT mg MR, pooled analysis of 12wk European 16 phase III studies including [15] RCT mg MR, 13wk 21 RCT mg MR dose titration, 13wk 21 RCT mg MR, 13wk 22 RCT mg MR dose titration, 13wk 22 RCT mg MR, 12wk 47 Continued next page 294 van Dijk et al.

9 Table III. Contd Study type No. of patients Abnormal ejaculation (% patients) Description a Reference active treatment comparator active treatment comparator RCT mg MR, 4wk, study in spinal cord injury 69 RCT mg MR dose titration, 4wk, study in spinal 69 cord injury RCT mg MR, 1y double-blind extension of [21] 74 RCT mg MR, 1y double-blind extension of [21] 74 RCT mg MR, 12wk 75 RCT mg OCAS, 12wk 75 RCT mg OCAS, 12wk 75 RCT mg MR, 12wk, comparator was alfuzosin 19 (3 2.5mg) RCT mg MR dose titration, 8wk, comparator 72 was doxazosin (1 x 4 8mg GITS dose titration) RCT mg MR, 57d, comparator was terazosin 63 (1 1 5mg dose titration) RCT mg MR, 1y, comparator was seronoa 17 repens (320mg) RCT mg MR, 1y, comparator was finasteride 54 (5mg) OLS mg MR, 6mo 55 OLS mg MR, up to 4y open-label extension 20 of [15,18,19] OLS Pooled data for mg MR, open-label 23 extension of [21,22] for up to 2y OLS mg MR, 1y open-label extension of 69 RCT reported in same article Terazosin RCT mg dose titration, 1y 24 RCT mg dose titration, 1y 76 RCT mg dose titration, 57d, comparator was 63 tamsulosin (1 x 0.4mg MR) a Drug doses refer to the immediate-release formulation of a drug, comparator refers to placebo, and data are from benign prostatic hyperplasia patients unless otherwise noted. GITS = gastrointestinal therapeutic system formulation; MR = modified-release formulation; OCAS = oral controlled absorption system formulation; OLS = open-label study; RCT = randomised controlled trial; SR = sustained-release formulation; XL = extended-release formulation. Effects of α1-adrenoceptor Antagonists on Male Sexual Function 295

10 296 van Dijk et al. low in doxazosin- and placebo-treated patients (ta- database of 12 European and US clinical studies ble III). The data for terazosin are less clear since found that BPH symptom improvement was slightly one RCT reports more abnormal ejaculation than better in patients experiencing abnormal ejaculation with placebo, whereas another reports less (table than in those without. While some patients discon- III). tinued studies as a result of abnormal ejaculation, the overall long-term adherence to treatment rate In contrast, a greater incidence of abnormal ejacwas higher in those with abnormal ejaculation than ulation than with placebo was seen in most studies in those without (e.g. 1 year: 71.9% vs 51.5%; 5 with tamsulosin, both in BPH and in spinal cord years: 39.8% vs 12.7%). injury patients (table III). While the incidence with [79] placebo never exceeded 1%, reported tamsulosin We are aware of four RCTs that have directly values range between 0.0% and 26%. In this regard, compared abnormal ejaculation among α-blockers. reported incidences were generally higher in the Two studies comparing tamsulosin MR 0.4mg once longer studies and in US than in European studies daily to either alfuzosin 2.5mg thrice daily [19] or ( % vs 4.5% in US vs European registration alfuzosin XL 10mg once daily [47] reported numeristudies with tamsulosin MR 0.4mg once daily). cally higher incidences of abnormal ejaculation with Moreover, the incidence of abnormal ejaculation tamsulosin, but the difference failed to reach statistiappeared dose dependent in both European [73] and cal significance in either study with pa- US studies, [21,22] with the highest incidences being tients per group. A randomised but open-label comreported with tamsulosin MR 0.8mg once daily. The parison of tamsulosin MR with terazosin in about OCAS formulation of tamsulosin, which has recentgreater 1000 patients per study arm reported a significantly ly been introduced in some countries, appeared to be incidence of ejaculation failure with tam- associated with slightly less abnormal ejaculation sulosin. [63] Finally, one double-blind RCT compared than the MR formulation in one RCT. [75] OLS (ex- tamsulosin 0.2mg once daily (the standard dose in cept those that were open-label extensions of the Japan) with silodosin 4mg (formerly known as controlled studies) reported lower incidences of abα1a-adrenoceptors KMD-3123, a drug with even greater selectivity for normal ejaculation (table III). Whereas a Spanish than tamsulosin) and placebo, OLS with 2740 patients reported study withdrawal and reported considerably more abnormal ejaculadue to abnormal ejaculation in 0.5% of tamsulosin tion with silodosin than with tamsulosin (22.3% vs MR-treated patients, [77] an analysis of the manufacturer-independent 1.6%). [80] prescription event monitoring The US package inserts list abnormal ejaculation database in the UK reported ejaculatory failure in as an adverse event of tamsulosin [27] but not of any 2% of finasteride-treated patients but only in four of other α-blocker [25,26,28] used in the treatment of BPH of tamsulosin-treated patients. [62] To better or hypertension. Taken together, abnormal ejaculaunderstand tamsulosin-associated abnormal ejacula- tion was reported more frequently in studies with tion, secondary analyses have been performed in tamsulosin than in those with other α-blockers. some of the studies. A pooled analysis of the Euro- However, the magnitude of the differences was too pean phase III studies found abnormal ejaculation to small to reach statistical significance in directly be more frequent in patients aged <65 years (6.3%) comparative studies with other α-blockers unless than in those aged >65 years (2.6%), whereas the very large groups were investigated. Moreover, abincidence in the placebo group was similar in both normal ejaculation was not frequently observed in age groups ( %). [78] In support of this age OLS with tamsulosin and did not lead to overall effect, it should be noted that the highest incidence greater study withdrawal. Since abnormal ejaculaof abnormal ejaculation ever reported was in a tion is present in >50% of men aged 60 years, [9] the clinical pharmacology study with young (aged 25 clinical relevance of a small further increase remains years) volunteers. [67] A combined analysis of the to be determined.

11 Effects of α1-adrenoceptor Antagonists on Male Sexual Function Other Sexual Adverse Effects was reported; 2434 of those men were sexually active and willing to answer the Danish Prostate While sexual desire, erectile function and ejacu- Symptom Score sexual function questionnaire latory function have been studied relatively fre- (DAN-PSSsex). [50] At the endpoint, the mean quently in the context of α-blocker use, there are weighted score had improved for stiffness of erecmany other ways to look at sexual function. Moreo- tion, amount of ejaculate and painful ejaculation ver, some studies have asked patients for global relative to baseline. satisfaction scores relating to their sexuality, a ques- One placebo-controlled study on doxazosin (dose tion that integrates the various domains. In this section, we discuss information related to these othstated that no clinically significant changes in sexu- titration up to 4mg) did not report specific data but er domains for the individual drugs. Several OLS have been performed with various al function were reported in 67 patients. [85] In an formulations of alfuzosin. One study with 7093 pa- RCT comparing the immediate-release with the tients receiving alfuzosin 2.5mg thrice daily for 1 GITS formulation of doxazosin (but not involving a year used a questionnaire including questions relatstudied in detail using the International Index of placebo arm), drug effects on sexual function were ed to sexual arousal, erection and satisfaction with sex life. The authors did not report specific Erectile Function. [61] Compared with baseline valresults but state that the three questions on sexualicant ues, the GITS formulation had statistically signifi- ty did not improve much relative to baseline. [81] improvements of intercourse satisfaction and Another OLS with 5849 patients receiving alfuzosin sexual satisfaction, whereas the immediate-release 2.5mg thrice daily for 1 year calculated a total formulation had statistically significant worsening sexual score (ranging from 0 to 30 points) based on of erectile function; neither drug had significant the same questions and reported this to have im- effects on orgasmic function or sexual desire. The proved by points in various subgroups of US package insert lists sexual dysfunction (not patients stratified for age and baseline score. The specified further) as an adverse event in 2% of greatest improvements were seen in younger pa- doxazosin- versus 1% of placebo-treated hypertentients (aged <65 years) and those with a severe sive patients. [26] baseline score, and the smallest improvement in old A pooled analysis of several European studies patients (aged >74 years) and those with a mild with tamsulosin shows a significant improvement of baseline score. [82] A regression to the mean phenomtotal sexual function score relative to placebo. enon is likely to have contributed to the greater [16] This score was also improved by tamsulosin MR in a improvements in subjects with worse baseline comparator study [16] and in a large 6-month OLS, symptoms. In a 3-year follow-up of the same cohort [55] (retaining 55% of the original patients), it was reanother RCT, 25 patients received tamsulosin MR neither of which involved a placebo arm. As part of ported that patients perceived sexual life score improvement was strongly inversely correlated with for 3 months and their sexual function was assessed age and with initial symptom severity, but few by the Urolife questionnaire, which was not altered relative to baseline. [86] specific data were given. [83] Another OLS from the A 1-year RCT comparing same investigators reported 1-year results on 2829 tamsulosin with finasteride used a non-specified six- patients receiving originally alfuzosin 2.5mg thrice item sexual function score. While odds ratios were daily, which could be switched to alfuzosin SR 5mg numerically in favour of tamsulosin for five ques- twice daily after 6 months. [84] In this study, the tions and the total score, none of the differences above-mentioned 30-point sexual score improved relative to finasteride reached statistical signififrom a basal value of 8.8 to a final value of 13.0 after cance. [54] Finally, an open-label pilot study has in- 1 year. Finally, an OLS involving 3076 men treated vestigated the effects of tamsulosin MR in 98 men with the alfuzosin XL 10mg formulation for 1 year with orgasm-associated pain. Relative to baseline, a

12 298 van Dijk et al. statistically significant improvement was reported for pain on a visual analogue scale. [87] Few studies have directly compared multiple α- blockers with regard to other sexual adverse effects. A secondary analysis of a comparative study be- tween alfuzosin 2.5mg thrice daily and tamsulosin MR 0.4mg once daily reported a numerical worsening in a total sexual function score with alfuzosin, and a numerical improvement with tamsulosin, but the difference between the two treatments was not statistically significant. [16] Another study compared alfuzosin XL 10mg and 15mg with tamsulosin MR 0.4mg and placebo. Abnormal semen was reported in one of 158 patients with tamsulosin but in none of the other three groups. [47] Finally, a study comparing the alfuzosin with doxazosin reported other sexual male dysfunction in one of 99 patients receiving doxazosin and in none of the 93 patients receiving alfuzosin. [48] 6. Conclusions statistically significant unless very large patient numbers are compared, and the incidence of abnormal ejaculations in OLS is low. Therefore, the possibility of abnormal ejaculation with tamsulosin must be weighed against the unparalleled cardiovascular safety record of this agent [88] when choosing the most appropriate α-blocker for an individual patient. Acknowledgements Within the last 5 years, the authors have received research support, consultancy and/or speakers honoraria from the following companies marketing α-blockers: Astellas, Boehringer Ingelheim, Pfizer and Sanofi-Aventis. References Numerous studies have reported on possible adverse effects of α-blocker treatment on sexual function. Adverse α-blocker effects on sexual desire, erectile function, ejaculatory function and global sexual function occur in few patients only, and in some cases even improved functions have been reported. In this regard, it should be considered that the overwhelming majority of findings come from BPH patients, that is a condition with major effects on quality of life. When α-blockers improve BPH 163: symptoms, associated improvements of sexual function may reflect a generally improved perception of wellbeing. Therefore, caution needs to be applied when extrapolating findings from BPH to, for example, hypertensive patients, who have not been studied extensively in this regard. There appears to be little difference between α-blockers with regard to effects on sexual function. A notable exception is the effect of tamsulosin on ejaculatory function, now proposed to be (relative) anejaculation rather than retrograde ejaculation. While adverse effects of tamsulosin on ejaculatory function have been well documented, the magnitude of differences with other α-blockers is insufficient to be detectable as 1. Major cardiovascular events in hypertensive patients random- ized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (AL- LHAT). ALLHAT Collaborative Research Group. JAMA 2000; 283: Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: Rosen RC, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the Multinational Survey of the Aging Male (MSAM-7). Eur Urol 2003; 44: van Dijk M, Skrekas T, de la Rosette JJ. The association between lower urinary tract symptoms and sexual dysfunction: fact or fiction? Curr Opin Urol 2005; 15: Braun MH, Sommer F, Haupt G, et al. Lower urinary tract symptoms and erectile dysfunction: co-morbidity or typical aging male symptoms? Results of the Cologne Male Sur- vey. Eur Urol 2003; 44: Johannes CB, Araujo AB, Feldman HA, et al. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol 2000; 7. Arai Y, Aoki Y, Okubo K, et al. Impact of interventional therapy for benign prostatic hyperplasia on quality of life and sexual function: a prospective study. J Urol 2000; 164: Schou J, Holm NR, Meyhoff HH. Sexual function in patients with symptomatic benign prostatic hyperplasia. Scand J Urol Nephrol Suppl 1996; 179: Frankel SJ, Donovan JL, Peters TI, et al. Sexual dysfunction in men with lower urinary tract symptoms. J Clin Epidemiol 1998; 51: Hull EM, Lorrain DS, Du J, et al. Hormone-neurotransmitter interactions in the control of sexual behavior. Behav Brain Res 1999; 105: Van Kerrebroeck PE, Jardin A, Laval KU, et al. Efficacy and safety of a new prolonged release formulation of alfuzosin 10mg once daily versus alfuzosin 2.5mg thrice daily and placebo in patients with symptomatic benign prostatic hyper- plasia. ALFORTI Study Group. Eur Urol 2000; 37: Debruyne FM, Jardin A, Colloi D, et al. Sustained-release alfuzosin, finasteride and the combination of both in the treat-

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