Treatments for lower urinary tract symptoms due to benign prostatic hyperplasia can be evaluated by multiple metrics. A balance within the confines of patient expectations is key to determining the ideal treatment. A troubling adverse event for some patients is sexual dysfunction. Because the cohort of men who seek treatment of sexual dysfunction and lower urinary tract symptoms is essentially identical, these disease processes frequently overlap. This article considers potential pathophysiologic causes of dysfunction with treatment and attempts to critically review the available data to assess the true incidence of sexual adverse events with treatment.
Key points
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Sexual dysfunction in the cohort of men who seek treatment of lower urinary tract symptoms is common.
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Alpha blocker use frequently has effects on ejaculatory function with large difference in dysfunction rates based on medication selectivity.
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5-alpha reductase inhibitor use may precipitate a variety of sexual adverse events with a complicated and layered pathophysiologic process.
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Surgical treatments frequently cause retrograde ejaculation with variation in incidence rates depending on the surgical treatment or technique.
Introduction
Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) are a common consultation for most practicing urologists. Although treatment rightly focuses on relief of urinary symptoms, the offered medical and surgical treatments frequently have unwanted effects that provoke sexual dysfunction in the forms of erectile dysfunction (ED) or ejaculatory dysfunction (EjD).
Despite the high prevalence of sexual dysfunction in the cohort of men who frequently require treatment of LUTS due to BPH, sexual adverse events (AEs) of treatments are often inadequately assessed. These endpoints are often recorded by sporadic patient report and not by validated questionnaires. As a result, the true incidence and severity of ED or EjD with many of these treatments is only partially understood. Additionally, the effects of LUTS and increasing age on sexual dysfunction makes interpretation of changes during the study period more challenging because new onset dysfunction may be related to treatment or natural age-related decline.
This article considers potential pathophysiologic causes of dysfunction with treatment of LUTS due to BPH and attempts to critically review the available data to assess sexually related AEs.
Introduction
Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) are a common consultation for most practicing urologists. Although treatment rightly focuses on relief of urinary symptoms, the offered medical and surgical treatments frequently have unwanted effects that provoke sexual dysfunction in the forms of erectile dysfunction (ED) or ejaculatory dysfunction (EjD).
Despite the high prevalence of sexual dysfunction in the cohort of men who frequently require treatment of LUTS due to BPH, sexual adverse events (AEs) of treatments are often inadequately assessed. These endpoints are often recorded by sporadic patient report and not by validated questionnaires. As a result, the true incidence and severity of ED or EjD with many of these treatments is only partially understood. Additionally, the effects of LUTS and increasing age on sexual dysfunction makes interpretation of changes during the study period more challenging because new onset dysfunction may be related to treatment or natural age-related decline.
This article considers potential pathophysiologic causes of dysfunction with treatment of LUTS due to BPH and attempts to critically review the available data to assess sexually related AEs.
Medications
Alpha Blockers
Alpha receptors are found throughout the human body, mostly as part of vascular smooth muscle and stromal tissue. In humans, there are 3 subtypes of alpha1 receptors: 1a, 1b, and 1d. Alpha1a receptor subtype comprises approximately 70% of prostatic alpha1 adrenergic receptors, with alpha1b generally found in systemic vasculature, although it has also been identified in the prostate. Alpha1d receptors are found in the bladder and in the central nervous system where they may play role in central regulation of voiding.
Alpha blockers (ABs) act by reversibly inhibiting receptor activation and are considered a first-line treatment of LUTS experienced secondary to BPH. Having a firm understanding of receptor subtype and location helps explain the efficacy and side-effect profile of these commonly used drugs. The alpha1a subtype offers a promising target for lower urinary tract relaxation and obstruction relief, whereas action at 1b and 1d can produce systemic effects of vasodilation, including orthostatic hypotension and syncope. The different ABs are equally efficacious in reducing symptoms of BPH but differ in their side-effect profiles.
AB medications can be roughly divided into selective and nonselective types. Third-generation ABs such as silodosin and tamsulosin have selective blockade, with silodosin acting specifically at alpha1a receptors and tamsulosin acting at both 1a and 1d. Nonselective ABs such as doxazosin and terazosin are not subtype specific and thus lead to more systemic side effects (headache, nasal congestion, syncope, orthostatic hypotension). These 2 medications produce fewer sexual AEs but must be titrated to mitigate their effects on orthostatic hypotension and syncope. The exception to this is alfuzosin, which is a nonselective AB that produces fewer first-dose systemic effects and does not need to be dose-titrated.
The most common side effect of the ABs is EjD because alpha receptors are widely distributed in organs involved in the emission phase of ejaculation. However, the previously held notion that EjD was due to relaxation of the bladder neck leading to retrograde ejaculation has been challenged. Although there are studies that still support the paradigm of retrograde movement of seminal fluid into the bladder with AB use, increasing evidence points towards anejaculation as the root cause. Specifically, in vitro work on human vas deferens demonstrates alpha 1a receptor antagonism eliminates electrically induced contractions.
As outlined in the American Urologic Association (AUA) guidelines for the treatment of BPH, sexual function is irregularly reported in most large AB studies. A few studies to date have attempted to measure changes in sexual function beyond EjD in men taking ABs. See later discussion of nonselective and selective ABs as separate groups, and of studies comparing adverse effects between ABs.
Nonselective alpha blockers
The nonselective ABs include alfuzosin, terazosin, and doxazosin, and have a relatively low incidence of overall sexual dysfunction and EjD.
One of the most rigorous examinations of the effects of a nonselective AB on various aspects of sexual function comes from the Medical Therapy of Prostatic Symptoms (MTOPS) trial data. Five different domains of sexual function were examined using a validated questionnaire that was state of the art at that time. Doxasozin was the AB examined and minimal effects on sexual function were seen in subjects. In another trial looking at doxasozin in a randomized, controlled fashion, the incidence of EjD, decreased libido, and ED was not different between study and control groups with both reporting incidence of roughly 1%.
In an uncontrolled study, 10 mg alfuzosin taken once daily for 1 year displayed improved ejaculatory function when compared with baseline measurements. A study from the ALFORTI study group was a double-blind, controlled study that showed no significant difference in EjD, decreased libido, or ED between groups, adding further evidence to the low incidence of sexual side effects with nonselective ABs. Another open-label study of 538 men taking 10 mg alfuzosin once daily over 2 years showed a small improvement in international index of erectile function (IIEF) score with no statistically significant difference in EjD or ED.
Selective alpha blockers
More selective ABs, such as tamsulosin and silodosin, produce fewer systemic side effects but have a greater incidence of EjD. Multiple studies have demonstrated a subjective incidence of reported EjD between 4.5% to 11% with the 0.4 mg tamsulosin dose. However, there is no change in erectile function between treatment and placebo groups. Slight improvements were noted in sexual desire, although differences in overall sexual satisfaction were not seen.
There does seem to be a dose-EjD correlation in patients taking tamsulosin. This was verified in a 2003 Cochrane review that found EjD in 18% of patients taking 0.8 mg dose tamsulosin, 6% in 0.4 mg group, and 0% in patients taking 0.2 mg dose.
Theoretically, a drop in systemic blood pressure could induce ED, although studies examining changes in erectile function and ABs have not found an association. In a double-blind study over a 12 week period, tamsulosin was compared with placebo with a validated questionnaire. Although investigators found no difference in erectile function, they did note that men who were on tamsulosin had decreases in ejaculatory or orgasmic frequency and overall sexual satisfaction.
Due to ultra-selectivity of silodosin, reported EjD rates have been among the highest seen for ABs. In a pooled analysis of 3 randomized placebo-controlled studies consisting of almost 1500 subjects, silodosin lead to 22% of subjects reporting EjD compared with only 0.9% of placebo patients. A smaller, similar study in Japanese men found similar results with 22% of patients reporting EjD.
Comparisons of alpha blocker medications
Although effects on urinary symptoms are often marginally different between ABs, the unintended effects with regard to both sexual dysfunction and systemic effects can be pronounced.
In a study conducted by Hellstrom and Sikka, 48 healthy men were randomized to tamsulosin, alfuzosin, or placebo. In men taking 0.8 mg of tamsulosin, there was a 35% incidence of anejaculation, with 90% of men taking tamsulosin experiencing reduced semen volumes compared with only 21% of men on alfuzosin and 12.5% of men on placebo. No subjects in the alfuzosin or placebo groups suffered from anejaculation. A crossover study looking at tamsulosin and alfuzosin also found increased rates of EjD in patients treated with tamsulosin.
Chapple and colleagues reported EjD in a 3-arm study with 14.2% of subjects taking silodosin reporting symptoms compared with only 2.1% of those taking tamsulosin and 1.1% in the placebo group. In an attempt to gauge bother of the EjD, investigators looked at study discontinuation rates. Although statistical differences were not seen, more subjects discontinued the study in the silodosin group (5) than in the tamsulosin (1) or placebo (0) groups.
A meta-analysis by Gacci and colleagues compared different ABs and their relative risk of producing EjD in men with LUTS. In comparison with placebo, increased risk was found with silodosin (odds ratio [OR] = 32.5) and tamsulosin (OR = 8.58). Doxazosin and terazosin did not have increased risk for EjD compared with placebo. Tamsulosin demonstrated less risk than silodosin in a direct comparison (OR = 0.09). Meta regression showed that EjD was associated with International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Qmax) both before and after treatment, although analyses also showed that EjD was independently associated with improvement in IPSS and Qmax. Table 1 summarizes the different AB study outcomes.
| Treatment | Subjects (Drug/Placebo) | ED (Drug/Placebo) | Decreased Libido (Drug/Placebo) | EjD (Drug/Placebo) |
|---|---|---|---|---|
| Alfuzosin 10 mg Qday | 143/154 | 0%/0.7% | 0%/0.7% | 0%/0% |
| Alfuzosin 2.5 mg TID | 150/154 | 0%/0.7% | 0.7%/0.7% | 0%/0% |
| Doxazosin | 275/269 | 5.8%/3.3% | 3.6%/1.9% | 3.6%/1.9% |
| Doxazosin | 3652/3489 | 3.56%/3.32% | 1.56%/1.4% | 1.1%/0.83% |
| Silodosin | 176/89 | — | — | 22%/0% |
| Silodosin , a | 466/457 | — | — | 28%/0.9% |
| Silodosin , a | 847/647 | 0.7%/0.3% | 0.5%/0.2% | 22%/0.9% |
| Tamsulosin 0.4 mg | 244/239 | — | — | 11%/<1% |
| Tamsulosin 0.8 mg | 248/239 | — | — | 18%/<1% |
| Tamsulosin | 381/193 | 0.8%/1.6% | 1%/0% | 4.5%/1% |
| Terazosin | 305/305 | 6%/5% | 3%/1% | 0.3%/1% |
5-Alpha Reductase Inhibitors
Postulating a physiologic basis to sexual dysfunction
5-alpha reductase inhibitors (5ARIs) competitively inhibit the enzyme 5-alpha reductase (5AR), which is responsible for the conversion of testosterone to dihydrotestosterone (DHT). In the human body, there are 3 forms of the enzyme (types 1, 2, and 3), each concentrated in different organs and tissue types throughout the body. Although systemic AEs of 5ARI use are less often reported than those of AB, there is growing evidence of 5ARI action outside of the prostate.
The effects of 5ARIs primarily center on the augmentation of DHT levels but may have other indirect actions also. DHT is a potent androgen with important embryologic functions as well as functions in adults. Children born with 5AR deficiency demonstrate ambiguous genitalia and undermasculinization. In adults, physiological levels of DHT promote prostate growth with a reduction in these levels specifically associated with involution of the epithelial component of the prostate.
As more research emerges on the complex role androgens play in human physiology, a clearer picture of hormonal role in sexual function is beginning to unfold. Specifically, research has shown the androgens increase levels of nitric oxide (NO) synthase expression and DHT is more effective than testosterone at increasing expression, at least in rat models. NO plays a critical role in increasing blood flow to the genitalia through its vasodilatory actions, allowing for proper erectile and ejaculatory function. One research team has postulated that lower levels of DHT, and the ensuing drop off in NO, lead to a deterioration in erectile function. This theory has been corroborated by improvement in erectile quality in studies involving DHT supplementation in men.
One explanation for the systemic, nonurologic effects of 5ARIs is the unintended influence of molecules called neurosteroids. 5ARIs not only prevent the conversion of testosterone to DHT but also inhibit the conversion of progesterone and deoxycorticosterone to their downstream important neurosteroid products. Psychological functions of neurosteroids are still being investigated but they have been postulated to have effects on mood, sleep, memory, anxiety, and sexual function. Finasteride has demonstrated the ability to cross the blood-brain barrier and gain access to the central nervous system, where it could possibly affect the cognitive aspects of sexual drive and pleasure.
Further research is needed to elucidate this primarily associative relationship between 5ARI use and sexual dysfunction but it is a hypothesis and a not an unrealistic pathophysiology in the least. One specific example was a small study involving men treated with finasteride who were noted to have lower levels of 5AR neuroactive steroid levels in their cerebral spinal fluid. These products were associated with persistent sexual side effects and anxious or depressive symptoms. It is hoped that further work will shed light on the specific mechanisms involved between 5ARI use and unintended systemic effects.
Study-specific outcomes
The FDA has approved 2 5ARIs, finasteride and dutasteride, for the treatment of BPH. Dutasteride inhibits both type 1 and 2 enzyme subtypes and finasteride is specific to type 2. Selective inhibition of type 2 receptor has been shown to reduce serum DHT by 70% to 80%, with decreases in intraprostatic DHT levels by 85%. The dual inhibition of dutasteride is associated with both lower serum and intraprostatic DHT levels (90% and 95%) but also with a potentially more problematic side-effect profile. Unlike ABs, 5ARIs are more clearly associated with sexual dysfunction beyond EjD, specifically decreased libido and erectile function, which seems to be most prominent after 1 year treatment with plateaus afterwards.
Taking a general overview of large, placebo-controlled drug trials involving 5ARIs, multiple recurring themes are noted. Studies almost always use spontaneous, dichotomous (present or not present), subject-reported outcomes as opposed to validated questionnaires to assess change in sexual function. Most trial drug groups report a higher rate of symptoms in the active treatment group with regard to ED, EjD, and decreased libido. However, it should be noted that, although these differences are often statistically significant, usually there is less than a 3% difference in symptoms compared with placebo. Data from randomized, placebo controlled trials on 5ARIs can be found in Table 2 .
| Treatment | Subjects (Drug/Placebo) | ED (Drug/Placebo) | Decreased Libido (Drug/Placebo) | EjD (Drug/Placebo) |
|---|---|---|---|---|
| Dutasteride | 126/127 | 0%/1% | 2%/0% | — |
| Dutasteride | 60/59 | 11%/3% | 4%/2% | — |
| Dutasteride | 2167/2158 | 1.7%/1.2% | 0.6%/0.3% | 0.5%/0.1% |
| Dutasteride | 4105/4126 | 9%/5.7% | 3.3%/1.6% | 1.4%/0.2% |
| Dutasteride 1 y | 1510/1441 | 6%/3% | 3.7%/1.9% | 1.8%/0.7% |
| Dutasteride 2 y | 1510/1441 | 1.7%/1.2% | 0.6%/0.3% | 0.5%/0.1% |
| Finasteride | 1577/1591 | 6.6%/4.7% | 4%/2.8% | 2.1%/0.6% |
| Finasteride (1 mg) | 779/774 | 1.4%/0.9% | 1.9%/1.3% | 1%/0.4% |
| Finasteride (1 mg) | 133/123 | 0.75%/0% | 1.5%/1.6% | 0%/0.8% |
| Finasteride (1 mg) | 286/138 | 3.8%/0.7% | 4.9%/4.4% | 2.8%/0.7% |
| Finasteride | 1759/583 | 5.6%/2.2% | 2.9%/1% | 2.1%/0.5% |
| Finasteride | 55/59 | 11%/3% | 13%/2% | — |
| Finasteride | 547/558 | 4.8%/1.8% | 3.8%/2.3% | 3.1%/1.1% |
| Finasteride | 768/737 | 4.5%/3.3% | 2.4%/1.4% | 1.8%/0.8% |
| Finasteride | 1736/579 | 8.1%/3.8% | 5.4%/3.3% | 4.0%/0.9% |
| Finasteride | 9423/9457 | 67.4%/61.5% | 65.4%/59.6% | 67.4%/61.5% |
| Finasteride | 1524/1516 | 5.1%/5.1% | 2.6%/2.6% | 0.2%/0.1% |
| Finasteride | 297/300 | 3.4%/1.7% | 4.7%/1.3% | 4.4%/1.7% |
| Finasteride | 310/303 | 15.8%/6.3% | 10%/6.3% | 7.7%/1.7% |
Most changes in sexual function associated with 5ARI use are usually noted to peak at 1 year of treatment. Differences between placebo and treatment groups become less pronounced after that time and are often the same at study termination if trials last beyond 2 years. Although the exact mechanism for this is difficult to explain, it may be related to natural progression of sexual dysfunction that comes with age, as was observed in the placebo control groups in the previously mentioned MTOPS study.
When comparing the reported percentages of sexual side effects experienced while taking either finasteride or dutasteride with those in placebo groups, sexual AEs rates seem to be higher in the medication with a narrowed enzyme target (finasteride). However, in a study with direct comparison of finasteride and dutasteride, side-effect reporting on impotence, decreased libido, EjD, and sexual function disorders were virtually identical. Both finasteride and dutasteride were equally effective in reducing prostate size and improving AUA-Symptom Index (SI) scores, including improvement in Qmax after 12 months of treatment. Another, smaller, study analyzed semen volume following treatment with either finasteride or dutasteride and found ejaculate volumes to be lower than placebo with 21% decrease and 24% decrease in finasteride and dutasteride groups, respectively. A meta-analyses comparison did not find differences with regard to EjD between these 2 medications.
An area of increased concern in the clinical management of patients taking 5ARIs for BPH is the persistence of AE beyond cessation of medication. One study examining the sexual AEs experienced by men taking 5 mg finasteride for 4 years had 4% of the drug group and 2% of the placebo group drop out of the study specifically due to sexual AEs. However, symptom resolution was infrequent in these men, with only 50% of the drug group reporting resolution of symptoms after medication cessation. Interestingly, men in the placebo group who discontinued the study reported symptom resolution in only 41% of cases. It should be noted that in analysis of the PLESS (Proscar Long-Term Efficacy and Safety Study) study, men treated with finasteride experienced new sexual AEs with an increased incidence only during the first year of therapy compared with placebo, once again highlighting a temporal relationship between side-effect severity and therapy course.
Further complicating the association of 5ARIs and sexual dysfunction is the provocative study looking at nocebo or the power of suggestion of sexual AEs and outcomes. In their study, investigators randomized subjects who were starting finasteride treatment to groups who either received no counseling on sexual AEs or were informed that the drug may “cause erectile dysfunction, decreased libido, problems of ejaculation but these are uncommon.” The investigators found that there was a significantly higher proportion of sexual dysfunction in the subjects informed of sexual side effects compared with those who were not informed (43.6% vs 15.3%) with increased rates of ED, poor libido, and EjD all reported in the group counseled on sexual AEs.
Combination of 5-Alpha Reductase Inhibitors and Alpha Blockers
A common combination therapy for LUTS due to BPH involves the concomitant use of a 5ARI along with an AB. Examination of study outcomes finds that, although the combination group generally has the best outcomes with regard to urinary symptoms (particularly in groups with the worst symptoms at baseline), the highest rates of sexual AEs also occur in the combination group. However, the larger contributor to the sexual AEs does seem to be the 5ARI and not the AB.
This is evidenced by the MTOPS data in which worsening ED, EjD, and libido were seen in the 5ARI (finasteride) and combination therapy groups (finasteride and doxazosin) but absent from the AB group. In their systematic review and meta-analysis, Gacci and colleagues found EjD was more common with combination therapy than with either ABs (OR = 3.75) or 5ARIs (OR = 2.7) alone. Fwu and colleagues found that combination therapy with doxazosin and finasteride produced the largest deterioration in EjD, erectile function, and overall sexual problems. As mentioned previously, these differences were most pronounced after 1 year of treatment and declined thereafter.
Phosphodiesterase Type 5 Inhibitors
The mechanism by which tadalafil and other phosphodiesterase type 5 inhibitors (PDE5is) provide relief of LUTS due to BPH is still in question. However, available basic science research and expert option hypothesize that the mechanism likely centers on a complex picture of modulation of the autonomic nervous system through NO and cyclic guanosine monophosphate (cGMP) activity. This may decrease prostatic tissue contraction as well as actions, including antiproliferation of prostate and bladder smooth muscle.
Thus far, only a few randomized controlled trials have investigated the efficacy of these medications for LUTS due to BPH, with many more studies demonstrating efficacy with regard to erectile function. For the obvious reasons, sexual AEs are unlikely with PDE5i considering their original indicated use in ED. Tadalafil is currently the only PDE5i with a dual indication for LUTS due to BPH and ED.
The daily dosing of tadalafil was investigated by Egerdie and colleagues at both the 2.5 mg and 5 mg daily dose. Both doses were well tolerated and, not surprisingly, erectile function scores improved. There were no safety concerns found by the investigators. Although multiple reports have quantified improvements in erectile function with daily tadalafil, few have rigorously examined change in ejaculatory function. In a study using the full IIEF, orgasmic function was also assessed along with ejaculatory frequency and orgasmic frequency. Interestingly, although there was a placebo arm, an active control group taking tamsulosin was included. More than 500 men were examined and improvements were noted in orgasmic function and ejaculatory frequency. Although these are encouraging, this is not the same as augmenting EjD because both of these outcomes could simply be related to an overall improvement in erection quality.
Anticholinergics
Anticholinergics have recently gained popularity as an adjunct therapy in the treatment of men with LUTS due to BPH. Although less frequently used as a first-line medication in men compared with use in women, this medication is commonly used to treat storage symptoms in men once voiding symptoms have been addressed with other medication classes. Anticholinergic medications act by blocking the choline receptor subtypes either in the urothelium or within the detrusor muscle. However, choline or muscarine receptor subtypes are found in multiple other parts of the body and unintended effects such as dry mouth, constipation, tachycardia, and neurologic changes are reported with varying frequency.
Only cursory assessments have been published in the urologic literature regarding the sexual side effects of anticholinergics in men. However, sporadic reports on anticholinergic properties in antidepressant medications demonstrate that provoked sexual dysfunction could be reversed with bethanachol.
Related posts:
The Epidemiology of Benign Prostatic Hyperplasia Associated with Lower Urinary Tract Symptoms
Diagnostic Work-Up of Lower Urinary Tract Symptoms
Alpha-blockers for the Treatment of Benign Prostatic Hyperplasia
Convective Water Vapor Energy for Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia
Bipolar, Monopolar, Photovaporization of the Prostate, or Holmium Laser Enucleation of the Prostate
Robotic-Assisted Simple Prostatectomy
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