Will Medical Management of Benign Prostatic Hyperplasia Result in Better or Worse Sexual Function in Men?

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1 Urol Sci 2011;22(1):14 18 MINI REVIEW Will Medical Management of Benign Prostatic Hyperplasia Result in Better or Worse Sexual Function in Men? Thomas I.S. Hwang 1,2,3 * 1 Shin Kong WHS Hospital, Taipei, Taiwan 2 School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan 3 School of Medicine, Taipei Medical University, Taipei, Taiwan Urinary symptoms of benign prostatic hyperplasia (BPH) may affect sexual function, considered by patients themselves to be one of the most important aspects of the disease. Though lack of consensus on the underlying mechanism involved, some hypothesis are accounted for this association, such as autonomic hyperactivity, decreased nitric oxide (NO) production in the prostate and penile cavernous muscle, as well as pelvic atherosclerosis and endothelial dysfunction. Although medical treatment with α-blockers and/or 5α-reductase inhibitors are the mainstays of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/ LUTS), there are some contradictory bias on the effect of sexual function either erectile or ejaculatory function. α-blocker is currently recommended as a first line treatment of BPH. Since it will reduce the sympathetic overstimulation of prostate, it may also affect the similar pathway in penis. It has been suggested that α-blockers may improve sexual function in patients with BPH. However, among α-blockers, tamsulosin is associated with an increased risk of ejaculation disorders. Long-term use of 5α-reductase inhibitors alone or combined with α-blockers will cause reduction of prostate volume and improved the clinical symptoms; however, it may associate with sexual problems, especially ejaculation disorders. Based on the already published data, the effect of α-blockers and 5α-reductase inhibitors on the sexual function will be reviewed. Moreover, this may reinforce physicians to manage appropriately these two highly prevalent and bothersome conditions. Accepted: October 16, 2010 KEY WORDS: α-blocker; 5α-reductase inhibitor; benign prostatic hyperplasia; erectile dysfunction; ejaculation *Corresponding author. Division of Urology, Department of Surgery, Shin Kong WHS Memorial Hospital, No. 95 Wen Chang Road, Shih Lin District, Taipei, Taiwan. M001009@ms.skh.org.tw 1. Introduction Pharmacological treatment has become the primary choice for symptomatic benign prostate hyperplasia (BPH), and it has been shown to be effective in improving short-term outcomes (maximal flow rate and symptom scores). The two principal drugs prescribed for BPH are α-blockers and 5α-reductase inhibitors. 1,2 Urologists are familiar with the nonsexual side effects of α-adrenergic blockers, as these effects are well documented. 2,3 However, some treatments for BPH may affect sexual function. 4 8 The sexual side effects, particularly ejaculatory dysfunction, are not as well studied, and there is even less information on the beneficial effects of these medications, particularly any positive effects on erectile function and sexual satisfaction. Medical treatment of BPH with finasteride may be Taiwan Urological Association. Published by Elsevier Taiwan LLC.

2 Medical treatment of BPH and sexual function associated with erectile dysfunction (ED) ( %). 4,5,7 However, α-blockade is not associated with this side effect. The beneficial effects of treatments for BPH need to be reported equally against the morbidities associated with these treatments. Some researchers believe that lower urinary tract symptoms (LUTSs)/BPH should be considered an independent risk factor for sexual dysfunction. 5,7 They concluded that older men can still have an active sexual life. 9,10 The severity of LUTSs has a direct impact on sexual disorders; therefore, sexual function should be considered when choosing BPH treatments. Most Asian men in the age group of years are sexually active, and over half of them are affected by sexual dysfunction. 5 However, a small study that enrolled 50 men with symptomatic BPH in Taiwan showed no obvious correlation between the International Prostate Symptom Score and International Index of Erectile Function-15 scores Adverse Effects on Sexual Function 2.1. Five alpha-reductase inhibitors Some clinical trials (VA, PROWESS, and PLESS) showed that 5α-reductase inhibitors such as finasteride can have adverse impacts on libido, potency, and ejaculatory function, which suggest a negative impact on the quality of life. 7,11 13 The probabilities of the occurrence of negative effects on sexual function with finasteride are 2 10% for decreased libido, 3 16% for ED (Table 1), and 0 8% for ejaculatory disorders. 7,14 The PROSPECT trial, involving 472 men who completed 2 years of therapy with finasteride, showed a 15.8% incidence of ED in the treatment arm vs. 6.3% in the placebo arm (p = 0.01). 15 Finasteride has also been shown to impair libido. In randomized clinical trials, the incidence of impaired libido with finasteride ranges from %. 16 Dutasteride, an inhibitor of both type 1 and 2 5α-reductase isozymes, has been investigated for treating BPH since The dual inhibitory effect of dutasteride produces nearly complete suppression of serum dihydrotestosterone in healthy male subjects. Abnormal ejaculation has been reported in a considerable number of patients (Figure 1) including a reduced ability to ejaculate, dry ejaculation, and painful ejaculation. 18 However, < 1% of patients discontinue the treatment because of such adverse events. 15,16 Ejaculatory dysfunction, like other sexual dysfunctions associated with finasteride, tends to occur earlier in the therapeutic duration. Most subjects experience symptoms within the first 9 months of treatment Alpha 1-blockers Blockade of α-receptors in the bladder neck causes muscle relaxation, which allows semen to flow back into the bladder during climax (retrograde ejaculation). The risk from α-blockade is generally < 1%, although it can be higher with certain agents such as tamsulosin. The pharmacological specificity of α-blockers varies according to the subtypes of α 1 -adrenergic receptors. The α 1A subtype appears to predominate in the bladder neck, prostatic smooth muscle, seminal vesicles, and vas deferens, and is involved in producing contractions. 19 Terazosin appears to be associated with a relatively lower incidence of ejaculatory dysfunction. The incidence of ejaculatory dysfunction with terazosin is 0.3%. 11 With alfuzosin, one study found no incidence of abnormal ejaculation. 20 Ejaculatory dysfunction with doxazosin has not been adequately studied. 21 In contrast, tamsulosin is associated with a significant incidence of ejaculatory dysfunction, which may be caused by its higher pharmacological selectivity for α 1A - receptors in the bladder neck, seminal vesicles, and vas deferens. In Chapple et al s trial, the incidence of ejaculatory dysfunction was 4.5% with tamsulosin vs. 1.0% with a placebo (p = 0.045). 22 Lepor et al. reported a 6.0% incidence of abnormal ejaculation in tamsulosin-treated patients, which was significantly higher than that with a placebo (p < 0.001). 23 Abnormal ejaculation is easily identified by a low ejaculate volume on semen analysis and a finding of sperm in the postejaculate urine. In all of the trials cited Table 1 Impact of 5α-reductase inhibitors on sexual function Side effects VA study, PROWESS study, PLESS study, 1-year follow-up 2-year follow-up 1-year follow-up Placebo Drug Placebo Drug Placebo Drug (n = 305) (n = 310) (n = 1591) (n = 1577) (n = 1376) (n = 1384) Decreased libido (%) Erectile dysfunction (%) Decreased ejaculation (%) NA NA NA NA Ejaculation disorders (%) NA = not available. VA = Veterans Affairs Cooperative Studies; PROWESS = PROscar Worldwide Efficacy and Safety Study; PLESS = PROscar Long-term Efficacy and Safety Study Group; PROSPECT = PROscar Safety Plus Efficacy Canadian Two-year Study. Vol. 22, 14 18, March

3 T.I.S. Hwang Percentage of pa ents Controls 5α-reductase inhibitor * 63 *p < * Reduced ability to ejaculate Delayed Dry Decreased force of Decreased amount of semen Painful Figure 1 Effect of 5α-reductase inhibitors on ejaculation dysfunction (MSHQ = Male Sexual Health Questionnaire). above, cessation of the medication resulted in resolution of symptoms of ejaculatory dysfunction. 3. Beneficial Effects on Sexual Function Several studies have shown a beneficial effect of α1- antagonists on overall sexual function. Kirby et al. reported that both doxazosin XL (extended release) and the standard dose improved sexual function in men with concomitant BPH and ED. 8 Kaplan et al. reported that additional doxazosin improved International Index of Erectile Function scores in patients for whom intracavernosal therapy had failed. 24 De Rose et al. attempted to use sildenafil combined with doxazosin for ED patients unresponsive to 3 months of sildenafil monotherapy. 25 They found that 11 of 14 patients (78.6%) showed a statistically significant increase in their International Index of Erectile Function scores. In addition, alfuzosin (10 mg) once daily has also been reported to improve sexual function in men with LUTSs and sexual dysfunction. 26 That study suggested that in patients with sexual dysfunction, alfuzosin may improve both erectile and ejaculatory dysfunction. Those improvements appeared to be strongly related to LUTSs and bothersome severity at baseline. Better improvement of erectile and ejaculatory function was observed in those patients who were severely affected (such as higher IPSS score and bothersome severity). The mechanism of how α 1 -blockers benefit sexual function remains to be elucidated. One possible explanation is that the improvement in LUTSs directly results in improvement in a patient s quality of life by reducing psychological stress and restoring self-image. 26 Recent experiments have shown that alfuzosin induces relaxation of the isolated rabbit corpus cavernosum, and this is exclusively mediated through blockade of smooth muscle α-adrenoreceptors. 27 It is well known that the sympathetic pathway plays a major role in penile detumescence and flaccidity through stimulation of postjunctional α 1 -receptors of corpus cavernosum smooth muscle cells. Recently, it was reported that the cavernosal noradrenaline level is significantly decreased in healthy men during erection but not in patients with ED due to different causes. Furthermore, it was postulated that the contractile response of corpus cavernosum smooth muscle cells mediated by adrenergic receptors increases with age. 28 Since increased sympathetic tone appears to be common in patients with BPH, this may explain the high prevalence of ED in such aging patients. However, recent experiments showed that alfuzosin induces relaxation of isolated rabbit corpus cavernosum, and this was exclusively mediated through blockade of smooth muscle α 1 adrenoreceptors Combined Therapy With a1-blockers and 5a-reductase Inhibitors Combined therapy with 5α-reductase inhibitors and α1- blockers is more effective than monotherapy alone for improving symptoms, and long-term outcomes are impressive in men with moderate to severe LUTSs and prostatic enlargement ( 30 ml). 30 Moreover, combination therapy significantly decreases the 4-year incidence of a composite endpoint of progression compared with doxazosin, finasteride, or a placebo, although at 1 year, combination therapy is superior to finasteride monotherapy but not to doxazosin monotherapy. 29 Drug-related adverse events are numerically more common in combined therapy than with monotherapy, and these include ED (7.4%), retrograde ejaculation 16 Vol. 22, 14 18, March 2011

4 Medical treatment of BPH and sexual function (4.2%), altered (decreased) libido (3.4%), ejaculation failure (2.4%), decreased semen volume (1.8%), loss of libido (1.7%), and nipple pain (1.2%). 31,32 Overall, the profile of events for combination therapy is consistent with that reported for the two monotherapies. Tamsulosin and dutasteride effect ejaculatory function, although probably via different mechanisms (such as adrenoreceptors and androgen receptors). 33,34 This probably accounts for a greater than additive rate of ejaculatory dysfunction. Previous studies have shown that although the total number of drug-related adverse events was significantly greater in a combined group compared with that in either monotherapy group (α-blocker or 5α-reductase inhibitor), 5% of the men in each treatment group, including the combined group, withdrew from the study as a result of those events. Therefore, those events did not lead to a substantial discontinuation rate in this population of elderly men. 33,34 5. Conclusions Different medical therapies have greater or lesser effects on sexual function in patients with BPH. Tamsulosin causes retrograde ejaculation, while 5α-reductase inhibitors affect the libido, and cause ED and low-volume ejaculate. Despite the statistical significance of the reported side effects, they are still relatively uncommon. 6. Further Perspectives Sexuality in BPH patients needs to be further evaluated. Sexuality needs to be taken into consideration in the therapeutic strategy of BPH. Investigation of measurements for evaluation of patients sexual function is required. In conclusion, sexual function and satisfaction with sex and one s feelings need further investigation with respect to treatments for BPH. Acknowledgments This study was sponsored by a grant from Shin Kong Wu Ho-Su Memorial Hospital (SKH DR-16). References 1. 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