madman
Super Moderator
Medical Treatment of Benign Prostatic Hyperplasia (2022)
Alexander Plochocki, MD, MPH, Benjamin King, MD*
INTRODUCTION
Benign prostatic hyperplasia (BPH) and its associated is one of the most common diagnoses seen by the urologist, with previous studies estimating greater than half of the men have at least one symptom of lower urinary tract symptoms (LUTS),1 with the prevalence increasing as our population ages with the majority of men older than 70 having BPH/LUTS.2 Over the last 2 decades, we have seen a decrease in surgical management and an increase in medical BPH management across the United States, especially with increasing patient age at the time of diagnosis.3
An enlarged prostate by itself is not an indication for treatment, but it is rather the symptoms and impact on the quality of life (QoL) that bring patients to the urologist. While many of these symptoms may be mild, by the time a man presents to the urologist, they have generally crossed the threshold into bothersome. While the primary issue of BPH was first believed to be solely from bladder outlet obstruction (BOO), we know now that LUTS is more complex and a combination of both voiding and storage issues. The gold standard to assess LUTS is the international prostate symptom score (IPSS; Table 1), which has been validated extensively and features both voiding and storage symptoms (ie, overactive bladder). While symptom relief and patient perception of treatment efficacy is inherently subjective, a score improvement of 4 points is often considered a significant improvement in most men.4
ALPHA-ADRENERGIC ANTAGONISM
The prostate contains a large amount of smooth muscle which responds to alpha-adrenergic stimulation by increasing the prostatic urethral resistance, by blocking this stimulation we can induce relaxation to lessen bladder outlet resistance. The bladder and prostate contain mostly alpha-1 receptors which led to the development of our arsenal of selective blockers. While most alpha-1 blockers in use today are well-tolerated, their side effect profile stems from the alpha blockade both in the prostate and systemically. Generally, patients may experience retrograde ejaculation, rhinitis, and orthostatic hypotension. As the bladder contains alpha receptors, which can explain why overactive bladder (OAB) symptoms can be lessened. The exact physiology of this is unclear but is theorized to involve an increase in detrusor blood flow stimulated by the alpha blockade.5
The first selective alpha-1 blocker was tested as prazosin, which demonstrated effectiveness, but required twice-daily dosing.6 Prazosin is no longer used for LUTS but has interestingly found use in the treatment of posttraumatic stress disorder. Doxazosin and terazosin are selective alpha-1 blockers that are dosed daily, in general, they require a titration period to get to a full therapeutic dose and are not often first-line agents.7,8
Tamsulosin is arguably the most well-known alpha-1 blocker, it is not just alpha-1 selective, but uro-selective which allows it to maintain good symptom control with minimal side effects. Generally, you can expect symptom relief within a few days to a week of starting therapy. Tamsulosin has been studied extensively and has been shown to decrease IPSS by about 9.5 points.9 Tamsulosin is generally prescribed at a dose of 0.4 mg, ideally taken 30 minutes after the same meal every day. The dose can be increased to 0.8 mg daily for patients with breakthrough symptoms.
Alfuzosin and silodosin are additional uroselective agents that are able to be dosed daily and have been additionally shown to be effective. Silodosin may be associated with worse sexual side effects, but less chance of orthostatic hypotension.10,11
Doxazosin has a gastrointestinal therapeutic system (Doxazosin GITS) formulation of doxazosin mesylatethat provides a more sustained release of the drug, which allows patients to start the drug at a therapeutic dose and forego titration. Interestingly, this GITS formation has been shown in some studies to provide better symptom relief for patients with a similar side-effect profile.12 In a similar way to tamsulosin, you can start doxazosin GITS at 4 mg daily and titrate up to 8 mg daily for breakthrough symptoms.
As alpha-1 antagonists as a class will demonstrate effect within a few days, patients who were started on these drugs for acute urinary retention requiring catheterization should be continued on these medications for a few days before a trial without a catheter. The AUA guidelines suggest at least 3 days of treatment.13
Patients should be counseled that, any time after starting alpha-1 blockers, they are at an increased risk of developing floppy iris syndrome during cataract surgery. This has been noted even years after stopping alpha-1 blockade therapy, so any patient who has been on alpha-1 blockers for any period of time may be at risk.14
5-ALPHA REDUCTASE INHIBITION
BPH is hormonally mediated almost exclusively by prostatic levels of dihydrotestosterone (DHT) and suppression of DHT leads to decreased prostate volume and therefore less prostatic urethral compression. Testosterone is converted to DHT by steroid 5-alpha reductase; there are 2 isozymes expressed in the body: Type 1 steroid 5-alpha reductase (predominately expressed in extraprostatic tissues) and type 2 steroid 5-alpha reductase (predominately expressed in prostatic tissues).
Finasteride (selective type 2 steroid 5-alpha reductase) and dutasteride (nonselective inhibitor of both isozymes) are the two 5-alpha reductase inhibitors (5ARIs) available. Given that these medications work on hormonal expression in the prostate, there is a significant lag time until symptom relief, patient’s should expect to wait 6 months to see results. Additionally, generally, patients with larger prostates will see better results.15 The AUA guidelines suggest using a 30 cc prostate as the lower cut-off for starting 5ARI therapy.13 Prostate size can be estimated with cross-sectional imaging, or estimated with digital rectal examination.
Finasteride and dutasteride have been extensively studied independently and head-to-head and found to decrease IPSS scores and decrease prostate volume by about 30%.16,17 There is no difference in outcomes or side effects with either medication. Side effects are usually well-tolerated and include erectile dysfunction (8.1%), decreased libido (6.4%), ejaculatory dysfunction (0.8%) gynecomastia (0.5%), all of which seem within the first year of treatment. Studies have shown that the incidence of side effects does not increase with longer treatment periods, with the exception of ejaculatory dysfunction, which did worsen with longer treatment.18 Interestingly, there is an increased reported incidence of “post-finasteride syndrome” which is characterized by sexual side effects and mood depression that persists despite drug cessation irrespective of the length of treatment, the pathophysiology of this is unclear, and it is an area of current research.19
The MTOPS trial demonstrated the safety and efficacy of 5ARI and alpha-1 antagonist combination therapy with men having less symptom progression on combination therapy compared with monotherapy. Men on finasteride alone or on combination therapy exhibited a decrease in rates of acute urinary retention and need for surgical intervention compared with doxazosin monotherapy.17 It is hypothesized that as men continue to age, their prostatic growth continues to cause increased urethral pressure that outpaces the effect of the 5ARI and the reduced smooth muscle relaxation of the alpha-1 antagonist;17 however, it should always be noted that as men age they may develop more medical comorbidities that may make them more susceptible to urinary retention independent of their BPH.
The controversial use of 5ARIs is in reducing prostatic bleeding associated with BPH either for gross hematuria with clot retention or given preoperatively before transurethral resection of the prostate (TURP). While there is significant anecdotal evidence for this use, there is a paucity of evidence-based data,20 but some studies suggest even short-term courses, on the order of 4 to 6 weeks, of 5ARIs may have clinical significance.21 Anecdotally, some urologists would continue patients on 5ARIs until a few weeks postop from a TURP and start it empirically on someone presenting with gross hematuria and LUTS.
ANTICHOLINERGICS
The detrusor muscle of the bladder is innervated by parasympathetic fibers and mediated through muscarinic receptors, which in turn mediates bladder capacity and involuntary detrusor contractions which can contribute to storage associated LUTS. By inhibiting these with muscarinic receptor antagonists (anticholinergics), we can decrease involuntary detrusor contractions, which in turn lead to better urine storage capacity. As we are inhibiting detrusor contractions, there is a risk of urinary retention, especially in patients with voiding LUTS.22
Oxybutynin, solifenacin, and tolterodine are 3 of the most commonly prescribed anticholinergics. While they do serve a role for patients with only overactive bladder symptoms, patients with BPH often have a combination of voiding and storage LUTS. Therefore, anticholinergics are often not used as monotherapy, as studies have shown that this can be far less effective than combination therapy.23 However, patients on tolterodine ER monotherapy were noted to have decreased urinary urgency incontinence without an increase in rates or urinary retention.
While acute urinary retention (AUR) is the oft-cited side effect of anticholinergics, the actual rates AUR have been quite low across the literature, likely on the magnitude of 0.3%.24 Generally, a cut-off PVR off 200 ccs has been used as a soft contraindication to starting anticholinergic therapy, which should obviously be stopped if a patient develops AUR. If a patient does develop AUR, we would not routinely trial a different anticholinergic. The most common side effects are dry mouth, constipation, and blurry vision. It should be noted that CNS side effects, such as confusion and delirium are more common in older men and men with preexisting neurologic conditions, and should be used with caution. There has been data to suggest that CNS side effects vary based on the drug, with one study demonstrating oxybutynin has worse CNS adverse events in comparison to darifenicin.25
Combination therapy for anticholinergics and alpha-1 antagonists has been proven to be successful with many different combinations of drugs. Tamsulosin and tolterodine ER were studied each as monotherapy, combined therapy, and compared with placebo; combination therapy was found to provide the most significant reduction in symptoms, with a larger reduction in storage symptoms, with no effect on urinary retention rates.23 This is further supported by a meta-analysis of multiple studies of different combinations of anticholinergic 1 alpha-1 antagonist combination therapy that support that patients with storage-LUTS experience a significant decrease in symptoms without an increase in urinary retention rates, suggesting that over 100 patients would need to be treated with combination therapy to induce an additional case of urinary retention.26
PHOSPHODIESTERASE TYPE 5 INHIBITION
Phosphodiesterase type 5 inhibitors (PDE5i) are most widely known as a treatment of erectile dysfunction (ED), through their vasodilator effect by blocking cGMP breakdown and promoting nitrous oxide production. Patients taking PDE5i have been noted to have a decrease in LUTS. While the overall mechanism for this is unclear, possible theories include increased oxygenation of the bladder and prostate as well as possible bladder neck and prostatic smooth muscle relaxation.27,28 ED and LUTS are often coexistent in the aging male as well, so a drug that can target both would be ideal across this population.
Sildenafil was the first PDE5i studied29 and further research demonstrated that among men with a baseline IPSS greater than 10, taking sildenafil a mean of 2 times a week was associated with a statistically significant decrease in IPSS by 4.6 points.30 Given sildenafil’s on-demand dosing, this can create a difficult treatment regimen for men to take, further exacerbated by sildenafil’s poor absorption, requiring it to be taken on an empty stomach. So while the decrease in LUTS could be viewed as a potential added benefit, a more stable drug would be preferred for the primary treatment of LUTS
This is whereby tadalafil has an advantage, as it has a much longer half-life in the body and can be taken daily. After tadalafil was proven to be effective in reducing LUTS,31 a randomized controlled dose-finding trial-tested tadalafil 2.5, 5, 10, and 20 mg daily over a 12-week period. All men demonstrated decreases in IPSS, but a 5 mg daily dose was found to have the most favorable risk-benefit profile.32 Currently, tadalafil dosed at 5 mg daily is the only PDE5i with FDA approval for treatment of BPH/LUTS. It is recommended to take it at the same time every day and can be taken with or without food. While 5 mg is the most common dose, it can be titrated for men with refractory ED or LUTS, we generally do not titrate past 10 mg daily. Side effects of tadalafil are generally well-tolerated by most men and include headache, flushing dyspepsia, nasal congestion, myalgias, and back pain. The adverse effect rate is similar to sildenafil; however, myalgias and back pain may be more prevalent with tadalafil.33 As tadalafil does not have the ejaculatory dysfunction side effects of alpha-blockers, this may make it a more attractive first-line therapy in younger men who prioritize sexual function.
While tadalafil is not as well studied with combination treatment as drugs in other classes, a recent meta-analysis34 of tamsulosin and tadalafil combination therapy demonstrated overall very positive results, that combination therapy results in an improvement in IPSS (mostly with improvement in voiding symptoms), increase in Qmax, as well as has an ameliorating effect on the ejaculatory dysfunction of tamsulosin monotherapy when on combination therapy. The study did note that there were more patients that had to stop treatment due to adverse events in the combination therapy cohorts. Overall, tadalafil and tamsulosin can be recommended to patients, but a discussion on the possibility of worsening side effects and possibly a contingency plan to return to monotherapy.
BETA-3 ADRENERGIC AGONISM
Beta-3 adrenergic receptors are present in the bladder and their activation leads to smooth muscle relaxation in the detrusor, by activating these receptors we can induce bladder relaxation, and inhibit micro contractions of the bladder, which leads to increased storage and a decrease in storage LUTS.35 Animal-based studies suggest that beta3 agonists also induce relaxation of the urethra36 providing possible physiology for relief of voiding-LUTS. Given that beta-3 agonists use a completely different pathway than their anticholinergic counterparts, it allows us to treat storage LUTS with a different side effect profile.
Mirabegron is the primary beta-3 agonist available, and while initially studied in men and women with OAB, there has been data specifically looking at this drug in men with BPH and storage symptoms. Mirabegron has been studied against solifenacin and found to provide similar relief of urgency, frequency, and incontinence.37 Mirabegron doses of 50 mg and 100 mg demonstrated no change from placebo in worsening BOO, as patients’ detrusor pressures and max flow rate were unaffected by placebo. Patients demonstrated decreased frequency and urgency on mirabegron.38 Mirabegron is started at a dose of 25 mg daily and is increased to 50 mg after 4 to 8 weeks, while some studies tested doses up to 100 mg, most patients are only titrated up to 50 mg.
While mirabegron is well-tolerated, previous studies have shown that an increase in systolic blood pressure with mirabegron, should be avoided in patients with difficult to control hypertension. Additionally, the patient’s blood pressure should be monitored while starting and up titrating. Anecdotally, it has been difficult to get insurance approval for mirabegron without demonstrating prior failure or intolerance of anticholinergics, and it is for this reason that we recommend against starting mirabegron on inpatients with the plan to continue through discharge.
Vibegron received FDA approval for use in OAB in 2020 and has shown promising results and safety, with the EMPOWUR clinical trial studying vibegron against tolterodine ER was demonstrating a better reduction in urge incontinence and a comparable decrease in urgency.39 The study was extended to 40 weeks and demonstrated continued safety and efficacy.40 Vibegron is currently being studied for use in BPH with storage LUTS.
PHYTOTHERAPY
There are a plethora of naturally-obtained compounds marketed for LUTS; studying and comparing these drugs is difficult, especially as controlling for drug contents and formulations are difficult between studies, disrupting the reproducibility and generalizability of results. The most commonly seen treatment of BPH is arrangements of saw palmetto (Serenoa repens). Multiple meta-analyses have demonstrated that, while well-tolerated, saw palmetto does not afford any change in LUTS.41 Side effects are usually stomach/abdominal upset, diarrhea, nausea, headache, rhinitis, decreased libido, and there are no published drug-herb interactions.42 Pygeum (Pygeum africanum), the bark of an African tree, is purported to also decrease LUTS, but— again—there is a lot of inter-study variability. Pygeum is well-tolerated through many of their studies without any major side effects documented.42 Nettle (Urtica dioica) are the roots of an herbaceous wild plant found worldwide that has a paucity of data supporting its use but is generally well-tolerated without serious side effects.42 Rye grass pollen (Secale cereale) is microbially digested pollen that is then extracted, with the active ingredients not entirely known, some clinical trials suggest it may help with LUTS, with side effects mostly of gastrointestinal upset and skin rash. Pumpkin seed (Cucurbita pepo) has not been well studied as a BPH treatment but has no documented side effects.42 The complete list of phytotherapy options would be quite extensive, but most of these treatments have little clinical evidence of their efficacy but are usually well-tolerated; clinicians should advise their patients accordingly.
SUMMARY AND SUGGESTIONS
Given the vast spectrum of medication classes and drugs in each category, there is variation in treatment across urologists. For BPH/LUTS, we start our work up with a digital rectal examination, urinalysis, and history to rule out other non-BPH causes of LUTS, such as a urethral stricture. If patients have symptoms of urinary retention, we will get a postvoid residual in our office as well. Additionally, we discuss possible lifestyle management options such as caffeine cessation for storage-LUTS and limiting evening fluid intake for nocturia. For most men, our treatment starts with 0.4 mg of tamsulosin taken with dinner or nightly, which they can increase to 0.8 mg daily if they are getting a partial response and otherwise tolerating the medication well. Even if patients have predominately storage LUTS, we will often still start an alpha-1 antagonist before starting an anticholinergic. If the patient has very severe LUTS and a large prostate volume (>30 ccs), we also discuss starting finasteride concomitantly, with the tentative plan to withdraw tamsulosin at 12 to 18 months. For patients presenting with urinary retention due to BPH, we will also start finasteride and tamsulosin. The commonly prescribed drugs and their dosages can be found in Table 2 and we present our general workflow for the medical management of BPH in Fig. 1.
Alexander Plochocki, MD, MPH, Benjamin King, MD*
INTRODUCTION
Benign prostatic hyperplasia (BPH) and its associated is one of the most common diagnoses seen by the urologist, with previous studies estimating greater than half of the men have at least one symptom of lower urinary tract symptoms (LUTS),1 with the prevalence increasing as our population ages with the majority of men older than 70 having BPH/LUTS.2 Over the last 2 decades, we have seen a decrease in surgical management and an increase in medical BPH management across the United States, especially with increasing patient age at the time of diagnosis.3
An enlarged prostate by itself is not an indication for treatment, but it is rather the symptoms and impact on the quality of life (QoL) that bring patients to the urologist. While many of these symptoms may be mild, by the time a man presents to the urologist, they have generally crossed the threshold into bothersome. While the primary issue of BPH was first believed to be solely from bladder outlet obstruction (BOO), we know now that LUTS is more complex and a combination of both voiding and storage issues. The gold standard to assess LUTS is the international prostate symptom score (IPSS; Table 1), which has been validated extensively and features both voiding and storage symptoms (ie, overactive bladder). While symptom relief and patient perception of treatment efficacy is inherently subjective, a score improvement of 4 points is often considered a significant improvement in most men.4
ALPHA-ADRENERGIC ANTAGONISM
The prostate contains a large amount of smooth muscle which responds to alpha-adrenergic stimulation by increasing the prostatic urethral resistance, by blocking this stimulation we can induce relaxation to lessen bladder outlet resistance. The bladder and prostate contain mostly alpha-1 receptors which led to the development of our arsenal of selective blockers. While most alpha-1 blockers in use today are well-tolerated, their side effect profile stems from the alpha blockade both in the prostate and systemically. Generally, patients may experience retrograde ejaculation, rhinitis, and orthostatic hypotension. As the bladder contains alpha receptors, which can explain why overactive bladder (OAB) symptoms can be lessened. The exact physiology of this is unclear but is theorized to involve an increase in detrusor blood flow stimulated by the alpha blockade.5
The first selective alpha-1 blocker was tested as prazosin, which demonstrated effectiveness, but required twice-daily dosing.6 Prazosin is no longer used for LUTS but has interestingly found use in the treatment of posttraumatic stress disorder. Doxazosin and terazosin are selective alpha-1 blockers that are dosed daily, in general, they require a titration period to get to a full therapeutic dose and are not often first-line agents.7,8
Tamsulosin is arguably the most well-known alpha-1 blocker, it is not just alpha-1 selective, but uro-selective which allows it to maintain good symptom control with minimal side effects. Generally, you can expect symptom relief within a few days to a week of starting therapy. Tamsulosin has been studied extensively and has been shown to decrease IPSS by about 9.5 points.9 Tamsulosin is generally prescribed at a dose of 0.4 mg, ideally taken 30 minutes after the same meal every day. The dose can be increased to 0.8 mg daily for patients with breakthrough symptoms.
Alfuzosin and silodosin are additional uroselective agents that are able to be dosed daily and have been additionally shown to be effective. Silodosin may be associated with worse sexual side effects, but less chance of orthostatic hypotension.10,11
Doxazosin has a gastrointestinal therapeutic system (Doxazosin GITS) formulation of doxazosin mesylatethat provides a more sustained release of the drug, which allows patients to start the drug at a therapeutic dose and forego titration. Interestingly, this GITS formation has been shown in some studies to provide better symptom relief for patients with a similar side-effect profile.12 In a similar way to tamsulosin, you can start doxazosin GITS at 4 mg daily and titrate up to 8 mg daily for breakthrough symptoms.
As alpha-1 antagonists as a class will demonstrate effect within a few days, patients who were started on these drugs for acute urinary retention requiring catheterization should be continued on these medications for a few days before a trial without a catheter. The AUA guidelines suggest at least 3 days of treatment.13
Patients should be counseled that, any time after starting alpha-1 blockers, they are at an increased risk of developing floppy iris syndrome during cataract surgery. This has been noted even years after stopping alpha-1 blockade therapy, so any patient who has been on alpha-1 blockers for any period of time may be at risk.14
5-ALPHA REDUCTASE INHIBITION
BPH is hormonally mediated almost exclusively by prostatic levels of dihydrotestosterone (DHT) and suppression of DHT leads to decreased prostate volume and therefore less prostatic urethral compression. Testosterone is converted to DHT by steroid 5-alpha reductase; there are 2 isozymes expressed in the body: Type 1 steroid 5-alpha reductase (predominately expressed in extraprostatic tissues) and type 2 steroid 5-alpha reductase (predominately expressed in prostatic tissues).
Finasteride (selective type 2 steroid 5-alpha reductase) and dutasteride (nonselective inhibitor of both isozymes) are the two 5-alpha reductase inhibitors (5ARIs) available. Given that these medications work on hormonal expression in the prostate, there is a significant lag time until symptom relief, patient’s should expect to wait 6 months to see results. Additionally, generally, patients with larger prostates will see better results.15 The AUA guidelines suggest using a 30 cc prostate as the lower cut-off for starting 5ARI therapy.13 Prostate size can be estimated with cross-sectional imaging, or estimated with digital rectal examination.
Finasteride and dutasteride have been extensively studied independently and head-to-head and found to decrease IPSS scores and decrease prostate volume by about 30%.16,17 There is no difference in outcomes or side effects with either medication. Side effects are usually well-tolerated and include erectile dysfunction (8.1%), decreased libido (6.4%), ejaculatory dysfunction (0.8%) gynecomastia (0.5%), all of which seem within the first year of treatment. Studies have shown that the incidence of side effects does not increase with longer treatment periods, with the exception of ejaculatory dysfunction, which did worsen with longer treatment.18 Interestingly, there is an increased reported incidence of “post-finasteride syndrome” which is characterized by sexual side effects and mood depression that persists despite drug cessation irrespective of the length of treatment, the pathophysiology of this is unclear, and it is an area of current research.19
The MTOPS trial demonstrated the safety and efficacy of 5ARI and alpha-1 antagonist combination therapy with men having less symptom progression on combination therapy compared with monotherapy. Men on finasteride alone or on combination therapy exhibited a decrease in rates of acute urinary retention and need for surgical intervention compared with doxazosin monotherapy.17 It is hypothesized that as men continue to age, their prostatic growth continues to cause increased urethral pressure that outpaces the effect of the 5ARI and the reduced smooth muscle relaxation of the alpha-1 antagonist;17 however, it should always be noted that as men age they may develop more medical comorbidities that may make them more susceptible to urinary retention independent of their BPH.
The controversial use of 5ARIs is in reducing prostatic bleeding associated with BPH either for gross hematuria with clot retention or given preoperatively before transurethral resection of the prostate (TURP). While there is significant anecdotal evidence for this use, there is a paucity of evidence-based data,20 but some studies suggest even short-term courses, on the order of 4 to 6 weeks, of 5ARIs may have clinical significance.21 Anecdotally, some urologists would continue patients on 5ARIs until a few weeks postop from a TURP and start it empirically on someone presenting with gross hematuria and LUTS.
ANTICHOLINERGICS
The detrusor muscle of the bladder is innervated by parasympathetic fibers and mediated through muscarinic receptors, which in turn mediates bladder capacity and involuntary detrusor contractions which can contribute to storage associated LUTS. By inhibiting these with muscarinic receptor antagonists (anticholinergics), we can decrease involuntary detrusor contractions, which in turn lead to better urine storage capacity. As we are inhibiting detrusor contractions, there is a risk of urinary retention, especially in patients with voiding LUTS.22
Oxybutynin, solifenacin, and tolterodine are 3 of the most commonly prescribed anticholinergics. While they do serve a role for patients with only overactive bladder symptoms, patients with BPH often have a combination of voiding and storage LUTS. Therefore, anticholinergics are often not used as monotherapy, as studies have shown that this can be far less effective than combination therapy.23 However, patients on tolterodine ER monotherapy were noted to have decreased urinary urgency incontinence without an increase in rates or urinary retention.
While acute urinary retention (AUR) is the oft-cited side effect of anticholinergics, the actual rates AUR have been quite low across the literature, likely on the magnitude of 0.3%.24 Generally, a cut-off PVR off 200 ccs has been used as a soft contraindication to starting anticholinergic therapy, which should obviously be stopped if a patient develops AUR. If a patient does develop AUR, we would not routinely trial a different anticholinergic. The most common side effects are dry mouth, constipation, and blurry vision. It should be noted that CNS side effects, such as confusion and delirium are more common in older men and men with preexisting neurologic conditions, and should be used with caution. There has been data to suggest that CNS side effects vary based on the drug, with one study demonstrating oxybutynin has worse CNS adverse events in comparison to darifenicin.25
Combination therapy for anticholinergics and alpha-1 antagonists has been proven to be successful with many different combinations of drugs. Tamsulosin and tolterodine ER were studied each as monotherapy, combined therapy, and compared with placebo; combination therapy was found to provide the most significant reduction in symptoms, with a larger reduction in storage symptoms, with no effect on urinary retention rates.23 This is further supported by a meta-analysis of multiple studies of different combinations of anticholinergic 1 alpha-1 antagonist combination therapy that support that patients with storage-LUTS experience a significant decrease in symptoms without an increase in urinary retention rates, suggesting that over 100 patients would need to be treated with combination therapy to induce an additional case of urinary retention.26
PHOSPHODIESTERASE TYPE 5 INHIBITION
Phosphodiesterase type 5 inhibitors (PDE5i) are most widely known as a treatment of erectile dysfunction (ED), through their vasodilator effect by blocking cGMP breakdown and promoting nitrous oxide production. Patients taking PDE5i have been noted to have a decrease in LUTS. While the overall mechanism for this is unclear, possible theories include increased oxygenation of the bladder and prostate as well as possible bladder neck and prostatic smooth muscle relaxation.27,28 ED and LUTS are often coexistent in the aging male as well, so a drug that can target both would be ideal across this population.
Sildenafil was the first PDE5i studied29 and further research demonstrated that among men with a baseline IPSS greater than 10, taking sildenafil a mean of 2 times a week was associated with a statistically significant decrease in IPSS by 4.6 points.30 Given sildenafil’s on-demand dosing, this can create a difficult treatment regimen for men to take, further exacerbated by sildenafil’s poor absorption, requiring it to be taken on an empty stomach. So while the decrease in LUTS could be viewed as a potential added benefit, a more stable drug would be preferred for the primary treatment of LUTS
This is whereby tadalafil has an advantage, as it has a much longer half-life in the body and can be taken daily. After tadalafil was proven to be effective in reducing LUTS,31 a randomized controlled dose-finding trial-tested tadalafil 2.5, 5, 10, and 20 mg daily over a 12-week period. All men demonstrated decreases in IPSS, but a 5 mg daily dose was found to have the most favorable risk-benefit profile.32 Currently, tadalafil dosed at 5 mg daily is the only PDE5i with FDA approval for treatment of BPH/LUTS. It is recommended to take it at the same time every day and can be taken with or without food. While 5 mg is the most common dose, it can be titrated for men with refractory ED or LUTS, we generally do not titrate past 10 mg daily. Side effects of tadalafil are generally well-tolerated by most men and include headache, flushing dyspepsia, nasal congestion, myalgias, and back pain. The adverse effect rate is similar to sildenafil; however, myalgias and back pain may be more prevalent with tadalafil.33 As tadalafil does not have the ejaculatory dysfunction side effects of alpha-blockers, this may make it a more attractive first-line therapy in younger men who prioritize sexual function.
While tadalafil is not as well studied with combination treatment as drugs in other classes, a recent meta-analysis34 of tamsulosin and tadalafil combination therapy demonstrated overall very positive results, that combination therapy results in an improvement in IPSS (mostly with improvement in voiding symptoms), increase in Qmax, as well as has an ameliorating effect on the ejaculatory dysfunction of tamsulosin monotherapy when on combination therapy. The study did note that there were more patients that had to stop treatment due to adverse events in the combination therapy cohorts. Overall, tadalafil and tamsulosin can be recommended to patients, but a discussion on the possibility of worsening side effects and possibly a contingency plan to return to monotherapy.
BETA-3 ADRENERGIC AGONISM
Beta-3 adrenergic receptors are present in the bladder and their activation leads to smooth muscle relaxation in the detrusor, by activating these receptors we can induce bladder relaxation, and inhibit micro contractions of the bladder, which leads to increased storage and a decrease in storage LUTS.35 Animal-based studies suggest that beta3 agonists also induce relaxation of the urethra36 providing possible physiology for relief of voiding-LUTS. Given that beta-3 agonists use a completely different pathway than their anticholinergic counterparts, it allows us to treat storage LUTS with a different side effect profile.
Mirabegron is the primary beta-3 agonist available, and while initially studied in men and women with OAB, there has been data specifically looking at this drug in men with BPH and storage symptoms. Mirabegron has been studied against solifenacin and found to provide similar relief of urgency, frequency, and incontinence.37 Mirabegron doses of 50 mg and 100 mg demonstrated no change from placebo in worsening BOO, as patients’ detrusor pressures and max flow rate were unaffected by placebo. Patients demonstrated decreased frequency and urgency on mirabegron.38 Mirabegron is started at a dose of 25 mg daily and is increased to 50 mg after 4 to 8 weeks, while some studies tested doses up to 100 mg, most patients are only titrated up to 50 mg.
While mirabegron is well-tolerated, previous studies have shown that an increase in systolic blood pressure with mirabegron, should be avoided in patients with difficult to control hypertension. Additionally, the patient’s blood pressure should be monitored while starting and up titrating. Anecdotally, it has been difficult to get insurance approval for mirabegron without demonstrating prior failure or intolerance of anticholinergics, and it is for this reason that we recommend against starting mirabegron on inpatients with the plan to continue through discharge.
Vibegron received FDA approval for use in OAB in 2020 and has shown promising results and safety, with the EMPOWUR clinical trial studying vibegron against tolterodine ER was demonstrating a better reduction in urge incontinence and a comparable decrease in urgency.39 The study was extended to 40 weeks and demonstrated continued safety and efficacy.40 Vibegron is currently being studied for use in BPH with storage LUTS.
PHYTOTHERAPY
There are a plethora of naturally-obtained compounds marketed for LUTS; studying and comparing these drugs is difficult, especially as controlling for drug contents and formulations are difficult between studies, disrupting the reproducibility and generalizability of results. The most commonly seen treatment of BPH is arrangements of saw palmetto (Serenoa repens). Multiple meta-analyses have demonstrated that, while well-tolerated, saw palmetto does not afford any change in LUTS.41 Side effects are usually stomach/abdominal upset, diarrhea, nausea, headache, rhinitis, decreased libido, and there are no published drug-herb interactions.42 Pygeum (Pygeum africanum), the bark of an African tree, is purported to also decrease LUTS, but— again—there is a lot of inter-study variability. Pygeum is well-tolerated through many of their studies without any major side effects documented.42 Nettle (Urtica dioica) are the roots of an herbaceous wild plant found worldwide that has a paucity of data supporting its use but is generally well-tolerated without serious side effects.42 Rye grass pollen (Secale cereale) is microbially digested pollen that is then extracted, with the active ingredients not entirely known, some clinical trials suggest it may help with LUTS, with side effects mostly of gastrointestinal upset and skin rash. Pumpkin seed (Cucurbita pepo) has not been well studied as a BPH treatment but has no documented side effects.42 The complete list of phytotherapy options would be quite extensive, but most of these treatments have little clinical evidence of their efficacy but are usually well-tolerated; clinicians should advise their patients accordingly.
SUMMARY AND SUGGESTIONS
Given the vast spectrum of medication classes and drugs in each category, there is variation in treatment across urologists. For BPH/LUTS, we start our work up with a digital rectal examination, urinalysis, and history to rule out other non-BPH causes of LUTS, such as a urethral stricture. If patients have symptoms of urinary retention, we will get a postvoid residual in our office as well. Additionally, we discuss possible lifestyle management options such as caffeine cessation for storage-LUTS and limiting evening fluid intake for nocturia. For most men, our treatment starts with 0.4 mg of tamsulosin taken with dinner or nightly, which they can increase to 0.8 mg daily if they are getting a partial response and otherwise tolerating the medication well. Even if patients have predominately storage LUTS, we will often still start an alpha-1 antagonist before starting an anticholinergic. If the patient has very severe LUTS and a large prostate volume (>30 ccs), we also discuss starting finasteride concomitantly, with the tentative plan to withdraw tamsulosin at 12 to 18 months. For patients presenting with urinary retention due to BPH, we will also start finasteride and tamsulosin. The commonly prescribed drugs and their dosages can be found in Table 2 and we present our general workflow for the medical management of BPH in Fig. 1.
