Hossein Sadeghi-Nejad, M.D., FACS
[Presented at Sexual Medicine Society of North America meeting in New Orleans, January 2005]
There is a rising tide of interest in exploring the relationship between lower urinary tract symptoms (LUTS) and sexual dysfunction in aging men. Important epidemiologic and basic science data have shed light on the links between these pathologies, but there is much to be learned about the pathogenetic relationship between LUTS and erectile dysfunction (ED). As in the relationship between hypertension and ED, the scientific challenge is made more difficult by the realization that it is possible, indeed likely, that both the pathology (i.e., BPH) and the therapies for the pathology (i.e., alpha blockers, 5 alpha reductase inhibitors, phytotherapies, transurethral resection, or minimally invasive heat-based therapies) may have a role in causing or exacerbating sexual dysfunction. This brief presentation is a summary of some of the current information on this topic. Furthermore, in a completely different and very interesting approach, Sairam et al investigated the relationsh! ip between ED and LUTS by assessing the effects of PDE5 inhibitors (sildenafil) on LUTS as measured by the International Prostate Symptom Score (IPSS). They reported that in men with ED, no relationship could be elicited between sexual function scores and urinary symptom scores before treating ED. However, treatment with sildenafil appeared to improve urinary symptom scores with better responses noted in those with lower IPSS at baseline.18 The slide presentation will include a brief review of the clinical implications of this finding as well as the hypotheses explaining the role of PDE5 inhibitors in alleviating LUTS.
MEDICAL AND PHYTOTHERAPIES
There is general agreement that phytotherapy (herbal treatment) for LUTS with Serenoa repens (saw palmetto) has a minimal detrimental effect on sexual function. In a systematic review of the effects of saw palmetto extracts for the treatment of benign prostatic hyperplasia (BPH), Wilt et al performed a meta-analysis of controlled randomized trials and reported erectile dysfunction in 1.1% of men taking saw palmetto.22 More recently, comparison of saw palmetto with placebo in a double-blind placebo-controlled randomized trial of 100 men with symptomatic BPH indicated that there was no significant adverse effect on sexual function as assessed by the International Index of Erectile Function (IIEF) scores.21 Interestingly, there was no significant beneficial effect of S. repens extract over placebo in symptom relief for BPH in this 12-week trial.
From a pharmacologic standpoint, the study of the effects of alpha-blockers on erectile function is most interesting. On one hand, the effects of alpha-blockers as intracavernosal erectogenic agents used in various combinations with alprostadil and papaverine (Bimix and Trimix) are well-known to most urologists. Since trabecular smooth muscle tone is strongly affected by alpha-adrenergic activity, inhibition of this activity is likely to cause smooth muscle relaxation and possible erectogenic activity. In vitro studies have not only demonstrated alpha adrenoreceptor activity in the corpus cavernosal smooth muscle, but have suggested the predominance of alpha-1 adrenoreceptors over alpha-2 receptors in human erectile tissue.17 In their review of alpha-receptors in relation to erectile function, Traish et al emphasize that multiple different regulatory influe! nces are at work and that different alpha-blockers will have different physiological responses in vivo.19 This unpredictability of "in vivo" activity is nicely summarized by McVary and McKenna who contrast the proerectile influence of alpha-blockers (alteration of the balance of vasoconstrictive and vasorelaxant forces to increase the latter) with the antierectile influence that may be caused by excessive hypotensive effects causing reduced penile filling pressure.14
A number of relatively recent studies have supported a role for alpha-blockers as potentially beneficial for patients with ED. For example, De Rose et al. evaluated the effects of 3 months of therapy with doxazosin on sexual activity and on voiding symptoms in 102 patients with BPH and reported a mild, but statistically significant increase in the IIEF score.6 Similarly, Kaplan et al evaluated the potential role of oral alpha-blockers (doxazosin titrated to 4mg) in combination with intracavernosal therapy in men with erectile dysfunction, for whom intracavernosal therapy alone failed. The authors reported that the combined regimen had a significant (more than 60% improvement in IIEF) therapeutic response.9 Despite these encouraging reports on the beneficial effects of alpha-blockers on erectile function, the results are far from unequivocal. For example, Lukacs et al. have reported improvements in health-related quality of life (HRLQ) measures and ! benefits in sexual functioning in men with severe nocturia treated with alfuzosin.12 However, it is unclear whether the improved sexual function is due to an undisturbed REM phase of sleep and more rest or the direct effect of alfuzosin on sexual function.2
Effective and accurate evaluation of many of the studies is further hampered by lack of standardization in use of various questionnaires and tools, as well as lack of unity in the definitions of "sexual dysfunction" in various papers (i.e. erectile dysfunction vs. retrograde ejaculation). The issue is particularly relevant to any study of alpha-blockers in relation to sexual dysfunction because of the known risks of ejaculatory dysfunction associated with certain alpha-blockers. Although the risk of retrograde ejaculation is low for certain alpha-blockers such as terazosin (0.3%- 1.4%), the overall incidence can be as high as 18.1% for the 0.8mg dose and 8.4% for the 0.4mg dose of tamsulosin.5,8
There have been two large, randomized, placebo-controlled, double-blind trials comparing safety and efficacy of finasteride (Proscar®) versus alpha-blockers in men with BPH.10,11 These studies, the VA Cooperative Study and PREDICT, reported similar incidence between treatment groups of adverse experiences relating to sexual/erectile function. In the VA Cooperative study, impotence was reported in 6% of the terazosin group and 9% of the finasteride group, and decreased libido was reported in 3% and 5%, respectively. In PREDICT, 5.8% of the doxazosin group and 4.9% of the finasteride group experienced impotence, while 3.6% and 3.4% experienced decreased libido respectively.
Bruskewitz et al reported the effects of finasteride on bother ("the degree that symptoms bothered men, interfered with their lifestyles, and caused worry or embarrassment about urinary function…") and health-related quality of life associated with benign prostatic hyperplasia. In this report, compared to placebo, men with symptomatic BPH and prostatic enlargement who received finasteride had slightly worse sexual satisfaction and sexual drive. Analysis of sexual function questionnaire data demonstrated that the differences between finasteride and placebo were primarily driven by men with baseline PSA < 1.4 ng/ml (smaller prostates).3
In the 4-year Proscar Long-term Efficacy and Safety Study (PLESS), comparison of year 1 with years 2 through 4 indicated that differences between finasteride and placebo relating to impotence and libido in year one disappear in years 2-4. Specifically, 3.7% of the placebo group and 8.1% of the finasteride group experienced erectile dysfunction in year 1 of the study, but both groups had a 5.1% incidence of erectile dysfunction in years 2-4.13 In the 2-year open extension follow-up study, for patients on continuous finasteride treatment, the decrease in incidence of acute urinary retention and/or BPH related surgery in the 4-year base study was sustained during the open extension and corroborated the findings of the original 4-year trial. Compared to those who remained on finasteride, there was a higher incidence of erectile dysfunction in patients who were switched from placebo to finasteride during the 2-year extension study (4.2% vs. 1.5%), but this was not ! unexpected and mimicked the earlier PLESS data in demonstrating a higher incidence of drug related adverse sexual experiences relative to placebo during year 1 of therapy.15 When all adverse sexual events were combined (impotence, decreased libido, ejaculation disorder, and gynecomastia) , the comparison between the groups demonstrated an incidence of 8% (switched from placebo to finasteride) vs. 3% (continuous finasteride). Currently, there are no satisfactory explanations for this decrease in incidence of sexual adverse events over time.
The effects of alpha-blockers and finasteride on erectile function were assessed in a real life scenario in a group of men with multiple risk factors for ED. A recent study of older men attending a Veterans Affairs clinic did not reveal a significant difference between the effects of terazosin or finasteride in causing ED in a group of men who had other risk factors for ED. The degree of ED as assessed by Sexual Health Inventory for Men (SHIM) scores was no different from an age-matched group of patients in the same clinic who were not on either medication, demonstrating the relatively greater importance of various other risk factors for ED. In this group of men with multiple risk factors for ED, age and other co-morbidities (heart disease, diabetes, hypertension, smoking, and hypercholesterolemia) appeared to have a much stronger influence than terazosin or finasteride on the severity of ED as assesse! d by SHIM scores.16
SURGICAL AND MINIMALLY INVASIVE THERAPIES
An evaluation of sexual function in patients with BPH before and after suprapubic prostatectomy revealed that age was the most significant factor for both urinary and sexual symptoms. Although comparative results between validated questionnaires did not show improvement in sexual scores after open surgery, sexual desire and overall satisfaction increased significantly.7 A prospective, randomized 1-year clinical trial comparing transurethral needle ablation (TUNA) to transurethral resection of the prostate (TURP) for the treatment of symptomatic benign prostatic hyperplasia by Bruskewitz et al documented some decrease in the amount of ejaculate volume from baseline in 54% of the resection group and 13% of the needle ablation group. The same study found a 12.7% incidence of ED in the resection group, but no evidence of ED in the TUNA cohort.4 The five year follow-up data demonstrated a 21.4% incidence of erectile dysfunction afte! r TURP as compared to 3.1% following TUNA. Retrograde ejaculation was reported in 41.1 % and 0% of the TURP and TUNA groups respectively.
In contrast, a prospective randomized evaluation of sexual function of LUTS patients before and after neodymium laser prostatectomy and transurethral resection of prostate with 1 year follow-up showed a high prevalence of erectile dysfunction (86%), ejaculatory volume change (83%) and pain or discomfort on ejaculation (26%) at baseline. With respect to ED, the number of men with ED changed from 2% at baseline to 12% post-operatively in the TURP group. In the laser group, the increase in ED was from 5% pre-op to 12% post-operatively. Whereas those with "no ejaculate" remained essentially unchanged before and after surgery in the laser group, there was a significant post-operative increase (from 10% to 71%) in the TURP group. The authors concluded that the only significant difference between these treatments with respect to sexual function was a higher incidence of decreased or absent ejaculate after TURP.20
Prospective evaluation of the impact of standard transurethral resection, transurethral microwave thermotherapy, interstitial laser coagulation and transurethral needle ablation of the prostate on sexual function showed a mild to moderate decrease in erectile function in 26.5%, 18.2%, 18.4% and 20.0% of the transurethral resection, microwave thermotherapy, laser coagulation and needle ablation groups, respectively, but there was no significant difference of mean pretreatment and post treatment erectile function or libido scores in any group. Ejaculatory dysfunction was reported by 48.6%, 28.1%, 21.6% and 24.3% of the patients, respectively. An important finding in this study was that whereas 45.5% of those with loss of ejaculation or severe decrease in ejaculate reported deterioration of their sex lives, only 3.6% of those without any change in ejaculate volume reported such deterioration, indicating a highly significant association between ejaculatory dysf! unction and an adverse impact on sexual activity.1
In summary, normal male sexual function may not only be affected by lower urinary tract symptoms and prostate pathologies, but by the various medical and surgical therapies for LUTS as well. Minimization of these adverse events is a challenge to be met by the clinician and the pharmaceutical industry. In the future, it will be interesting to see if both ED and LUTS can be successfully managed by one class of medication targeted against both pathologies.
- 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 164:1206, 2000
- 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 Survey". Eur Urol 44:588, 2003
- Bruskewitz R, Girman CJ, Fowler J, et al: Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology 54:670, 1999
- Bruskewitz R, Issa MM, Roehrborn CG, et al: A prospective, randomized 1-year clinical trial comparing transurethral needle ablation to transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia. J Urol 159:1588, 1998
- Carbone DJ, Jr., Hodges S: Medical therapy for benign prostatic hyperplasia: sexual dysfunction and impact on quality of life. Int J Impot Res 15:299, 2003
- De Rose AF, Carmignani G, Corbu C, et al: Observational multicentric trial performed with doxazosin: evaluation of sexual effects on patients with diagnosed benign prostatic hyperplasia. Urol Int 68:95, 2002
- Gacci M, Bartoletti R, Figlioli S, et al: Urinary symptoms, quality of life and sexual function in patients with benign prostatic hypertrophy before and after prostatectomy: a prospective study. BJU Int 91:196, 2003
- Hofner K, al e, Group ftETS: Tamsulosin 0.4 mg once daily: effect on sexxual function in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 36:335, 1999
- Kaplan SA, Reis RB, Kohn IJ, et al: Combination therapy using oral alpha-blockers and intracavernosal injection in men with erectile dysfunction. Urology 52:739, 1998
- Kirby RS, Roehrborn C, Boyle P, et al: Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 61:119, 2003
- Lepor H, Williford WO, Barry MJ, et al: The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med 335:533, 1996
- Lukacs B, Leplege A, Thibault P, et al: Prospective study of men with clinical prostatic hyperplasia treated with alfuzosin by general practitioners: 1-year results. Urology 48:731, 1996
- McConnell JD, Bruskewitz R, Walsh P, et al: The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 338:557, 1998
- McVary KT, McKenna KE: The relationship between erectile dysfunction and lower urinary tract symptoms: epidemiological, clinical, and basic science evidence. Curr Urol Rep 5:251, 2004
- Roehrborn CG, Bruskewitz R, Nickel JC, et al: Sustained decrease in incidence of acute urinary retention and surgery with finasteride for 6 years in men with benign prostatic hyperplasia. J Urol 171:1194, 2004
- Sadeghi-Nejad H, Sherman N, Lue J: Comparison of finasteride and alpha-blockers as independent risk factors for erectile dysfunction. Int J Clin Pract 57:484, 2003
- Saenz de Tejada I, Kim N, Lagan I, et al: Regulation of adrenergic activity in penile corpus cavernosum. J Urol 142:1117, 1989
- Sairam K, Kulinskaya E, McNicholas TA, et al: Sildenafil influences lower urinary tract symptoms. BJU Int 90:836, 2002
- Traish A, Kim NN, Moreland RB, et al: Role of alpha adrenergic receptors in erectile function. Int J Impot Res 12 Suppl 1:S48, 2000
- Tuhkanen K, Heino A, Aaltoma S, et al: Sexual function of LUTS patients before and after neodymium laser prostatectomy and transurethral resection of prostate. A prospective, randomized trial. Urol Int 73:137, 2004
- Willetts KE, Clements MS, Champion S, et al: Serenoa repens extract for benign prostate hyperplasia: a randomized controlled trial. BJU Int 92:267, 2003
- Wilt TJ, Ishani A, Stark G, et al: Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 280:1604, 1998