Symptomatic and urodynamic responses in patients with reduced or no seminal emission during silodosin treatment for LUTS and BPH

Prostate Cancer and Prostatic Diseases (2011) 14, 143–148 & 2011 Macmillan Publishers Limited All rights reserved 1365-7852/11 www.nature.com/pcan ORIGINAL ARTICLE Symptomatic and urodynamic responses in patients with reduced or no seminal emission during silodosin treatment for LUTS and BPH CG Roehrborn1, SA Kaplan2, H Lepor3 and W Volinn4 1 Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 2Department of Urology, Institute of Bladder and Prostate Health, Weill College of Medicine, Cornell University, New York, NY, USA; 3Department of Urology, New York University, New York, NY, USA and 4Clinical Research, Watson Laboratories, Salt Lake City, UT, USA Data from phase 3 studies (NCT00224107, NCT00224120) of silodosin for treatment of BPH symptoms were analyzed to examine the relationship between treatment efficacy and occurrence of abnormal ejaculation. Men aged X50 years with International Prostate Symptom Scores (IPSS) X13 and peak urinary flow rates (Qmax) of 4–15 ml s1 received placebo or silodosin 8 mg once daily for 12 weeks. Silodosin-treated patients were stratified by absence or presence of ‘retrograde ejaculation’ (RE). Groups were compared using analysis of covariance (for change from baseline) and responder analyses. Of the 466 patients receiving silodosin, 131 (28%) reported RE and 335 (72%) did not; 4 of the 457 patients receiving placebo (0.9%) reported RE. Most RE events in silodosin-treated patients (110/134; 82%) were reported as ‘orgasm with absence of seminal emission.’ Silodosin-treated patients with ( þ ) and without () RE showed significant improvement in IPSS, Qmax and quality of life versus placebo (Po0.02). RE þ patients versus RE patients experienced numerically greater improvement, but differences were not statistically significant (P40.05). For RE þ patients, the odds of achieving improvement of X3 points in IPSS and X3 ml s1 in Qmax by study end were 1.75 times those for RE patients (P ¼ 0.0127). Absence of seminal emission may predict superior treatment efficacy of silodosin in individual patients. Prostate Cancer and Prostatic Diseases (2011) 14, 143–148; doi:10.1038/pcan.2010.46; published online 7 December 2010 Keywords: BPH; LUTS; a-blocker; retrograde ejaculation; IPSS score Introduction Treatment with a-blockers has been shown to relieve BPH-related symptoms and improve urinary flow.1,2 a-Blockers are believed to act by inducing smooth muscle relaxation in the bladder neck, prostate and prostatic capsule through the blockade of a1-adrenergic receptors. A vast majority of a1-receptors in these tissues are thought to belong to the a1a-receptor subtype.1 The efficacy of providing symptom relief in patients with BPH-associated lower urinary tract symptoms (LUTS) is thought to be similar for all a-blockers, regardless of their selectivity for a1-receptor subtypes, including a1a-, a1b- and a1d-receptors.3 However, ablockers differ in their safety and tolerability profiles,4 particularly in their propensity to cause abnormal ejaculation.5 In controlled clinical trials, the percentage of patients treated with the moderately a1a-selective ablocker tamsulosin who reported abnormal ejaculation varied between 4 and 26%, depending on dose and study Correspondence: Dr CG Roehrborn, University of Texas Southwestern Medical Center, Department of Urology, 5323 Harry Hines Boulevard, J8.148, Dallas, TX 75390-9910, USA. E-mail: Received 6 June 2010; revised 13 September 2010; accepted 20 September 2010; published online 7 December 2010 duration.6,7 In a long-term open-label extension study, 30% of patients treated with tamsulosin reported abnormal ejaculation.8 In contrast, incidences of abnormal ejaculation related to the use of non-selective a-blockers, such as doxazosin, terazosin or alfuzosin, generally were lower than 1.5%.3 The Medical Dictionary for Regulatory Activities (MedDRA), the source for standard terminology for adverse events recorded in clinical trials, uses ‘retrograde ejaculation’ (RE) as an umbrella term to describe a broad spectrum of patient-reported events of abnormal ejaculation, including absence of seminal emission, reduced ejaculate volume and reduced ejaculation force. This terminology reflects the formerly common belief that abnormal ejaculation was mechanistically the result of RE. It was assumed that pronounced relaxation of the bladder neck muscle caused by blockade of a1a-receptors in this area would lead to backflow of seminal fluid from the prostatic urethra into the bladder. In contrast, contraction of the bladder neck during orgasm and rhythmic contraction of the bulbospongiosus muscle facilitate propulsive ejaculation in the normal antegrade manner. A recent placebo-controlled study that examined the effects of tamsulosin and the non-selective a-blocker alfuzosin on ejaculatory function in healthy volunteers found that tamsulosin 0.8 mg per day caused markedly reduced ejaculate volume in 90% of patients and Silodosin for LUTS and BPH CG Roehrborn et al 144 anejaculation in 35% of patients. However, analysis of post-climactic urine samples showed no increase in sperm counts, suggesting that RE did not occur.9 a1a-Receptors are abundant not only in the bladder neck but also in the vas deferens and seminal vesicle. Recently, it has been postulated that a1a-selective a-blockers cause reduced or absent seminal emission by inhibiting smooth muscle contraction in these genital tissues.10 Silodosin is a newly approved a-blocker with unique receptor subtype and tissue selectivity.11–13 Compared with tamsulosin, which has in vitro selectivities of 9.55 for human a1a versus a1b and B2.5 for a1a versus a1d, silodosin is 162 times more selective for a1a than for a1b, and is B55 times more selective for a1a than for a1d.14 In two 12-week randomized, placebo-controlled, multicenter US studies, silodosin significantly improved BPHrelated LUTS and peak urinary flow rate (Qmax).15 Results were consistent with the findings of clinical studies of silodosin in Japanese patients.12,16,17 Japanese and US phase 3 studies of silodosin reported high incidences of abnormal ejaculation. Overall, 28% of silodosin-treated patients in the two US studies reported abnormal ejaculation (classified as RE), as did 22.3% of silodosin-treated patients in the Japanese study.16 A recent study in healthy volunteers suggests that silodosin, similar to tamsulosin, induces the absence of seminal emission rather than true RE.18 If we assume that the efficacy of silodosin and its propensity to cause abnormal ejaculation are both attributable to the selective blockade of a1a-receptors, it is reasonable to hypothesize that treated patients who experience abnormal ejaculation may achieve greater symptom relief than those with no ejaculatory disturbances. In this post hoc analysis of data from two placebocontrolled US phase 3 trials of silodosin, we examined the relationship between clinical efficacy and the (...truncated)