madman
Super Moderator
ABSTRACT
Medical management of benign prostatic hyperplasia(BPH) has progressed gradually in recent years and remains the starting point for most symptomatic patients seeking treatment. Beyond well-known alpha-blockers and 5-alpha reductase inhibitors, there is growing evidence for the use of phosphodiesterase-5 inhibitors and beta-3 agonists in managing the condition, which may afford additional relief of “bothersome” symptoms in some patients. This review details the contemporary medical management of BPH with an emphasis on the indications for certain classes of pharmacotherapy and their relative benefits ts and side effects. Surgical and procedural treatment of BPH is covered in a separate review.
Benign prostatic hyperplasia (BPH), also known as benign prostate enlargement or obstruction, is a histologic diagnosis that describes the proliferation of glandular epithelial tissue and smooth muscle within the transition zone of the prostate.1,2 The prostate gland has both intrinsic and extrinsic factors that likely play complex roles in its growth. These include the interaction between the stroma and epithelium, hormone and androgen exposure (specifically testosterone and, more importantly, dihydrotestosterone), dietary factors, micro-organisms, and genetic predisposition.1,2
Although the exact mechanism for the development of BPH is unknown, age-related changes causing metabolic disturbances, changes in hormone balance, and chronic inflammation appear to contribute.3 Despite diminishing levels of testosterone as patients grow older, the amount of circulating dihydrotestosterone and prostatic androgen receptors remains high.2 The average prostate is approximately 20 cc between the ages of 21 and 30.BPH can begin to develop in the early 40s in some men and is found in 50% of men ages 51 to 60.3,4 The prevalence of BPH increases steadily with age, reaching 60% at age 60 and 80% at age 80.5 An enlarged prostate gland, while not in itself pathologic, can result in lower urinary tract symptoms, either by directly obstructing the bladder outlet as enlargement changes the shape of the gland or by increasing smooth muscle tone and resistance to flow within the enlarged gland.2
Lower urinary tract symptoms associated with BPH are characterized as disturbances in the retention of urine, voiding, and postmicturition state. These symptoms provide insight into the impact of BPH on patient quality of life.6,7 The International Prostate Symptom Score is a validated 8-point questionnaire that numerically characterizes patient symptoms.8–10 Three questions pertain to storage symptoms (frequency, nocturia, urgency), and 4 pertain to voiding (feelings of incomplete emptying, weak stream, intermittency, straining). The final question assesses the self-reported impact of symptoms on patient quality of life
The goal of treatment for lower urinary tract symptoms associated with BPH has long been to maximize quality of life and minimize “bothersome” symptoms. More recently, the focus on preventing side effects or treatment complications has been growing. This review outlines the most common medical treatments for lower urinary tract symptoms associated with benign prostatic hyperplasia.
■ DIAGNOSTIC EVALUATION
■ CONSERVATIVE MANAGEMENT
■ PHARMACOTHERAPY
Alpha-blockers
Alpha-blockers are a class of drugs first introduced in the late 1980s and early 1990s. They work by antagonizing alpha-1 receptors in the bladder neck and prostate, which results in the relaxation of smooth muscle in these areas,12–17 and in turn, reduced constriction of the urinary channel and lower resistance to urinary flow. 14 Despite a plethora of medications within this class, all are relatively equally effective, with an expected international Prostate Symptom Score improvement from a baseline of 3.7 to 7.1 points.13
The 5 main alpha-blocker medications include second-generation drugs (terazosin, doxazosin) and third-generation drugs (tamsulosin, alfuzosin, silodosin). The third-generation drugs are generally well-tolerated, and tamsulosin is associated with fewer side effects.12 The second-generation alpha-blocker medications require dose titration owing to their antihypertensive effects.12
The therapeutic effect of alpha-blockers starts within hours to days, although it generally takes 3 to 7 days to reach maximum effect.13–15,18 Common side effects include lightheadedness, dizziness, headache, nasal congestion, erectile dysfunction, and ejaculatory dysfunction or anejaculation (formerly known as retrograde ejaculation). These side effects usually accompany the therapeutic effect of the medication, are generally dose-dependent, and resolve within a few days with medication discontinuation. Ejaculatory dysfunction results from the relaxation of the smooth muscle within the prostatic and ejaculatory ducts with alpha blockade.19 This can be very distressing and bothersome for some and a relevant clinical concern for men who may want to father a child, as they may be unable to do so while using alpha-blockers.
5-alpha reductase inhibitors
Androgens are essential to prostatic growth.16 The conversion of testosterone to dihydrotestosterone, a more potent ligand for the androgen receptor and arbiter of prostatic growth is central to this process.14–17,22 Inhibiting the conversion of testosterone to dihydrotestosterone with 5-alpha reductase inhibitors(5ARIs) can reduce prostate growth and tip the scales toward prostatic cellular apoptosis and atrophy. Atrophy is more pronounced in the glandular epithelium of the prostate where PSA is made, as opposed to the smooth muscle stromal component of the gland. 23 Thus, gland composition (more glandular vs more stromal) may impact medication efficacy. The impact of 5ARIs on the glandular cells results in a decrease in PSA of approximately 50% after 6 to 12 months of treatment.16,22,23 Therefore, because PSA is a key predictor of treatment outcome, measurement of baseline PSA is recommended for all patients considering 5ARI therapy.
Owing to their mechanism of action and effect on gland size, 5ARIs should be reserved for patients with BPH and lower urinary tract symptoms who have prostate glands 30 cc or larger or palpable prostatic enlargement on digital rectal examination.16,23 Finasteride and dutasteride are the most commonly used 5ARIs.16,22,23 Finasteride inhibits the 5AR type II isoenzyme, while dutasteride inhibits type I and II isoenzymes.22 Because type II 5AR is more commonly found in prostate tissue, the clinical effect of these medications does not differ. Notably, 5ARIs require about 3 months of use before noticeable improvements in urinary symptoms occur, and approximately 6 months to reach full effect in terms of prostate volume reduction.16,22,23 It is critically important to explain to patients the expected timeframe to ensure medication adherence.
5ARIs for prostate cancer prevention have been studied for some time, with the evidence showing these medications reduce overall prostate cancer rates, particularly low-grade cancers. This is likely because fi finasteride reduces prostate volume, resulting in improved detection of cancer on prostate biopsy, and because of its selective inhibition of low-grade cancers.16,22 There is a black box warning regarding 5ARIs because they were thought to potentially increase the risk for higher-grade prostate cancers, but were later determined to be helpful in the process of detecting these cancers.5,16,22 These medications are regularly used and thought to be safe.
Side effects of 5ARIs vary widely across research studies but include bothersome symptoms related to testosterone deficiency including erectile dysfunction, ejaculatory dysfunction (reduced semen volume and thinned semen consistency), decreased libido, and possible fertility implications.5,24 Although a causal link between 5ARIs and infertility has yet to be elucidated, the 5-alpha reductase is physiologically active in human testes, with dihydrotestosterone promoting the expression of tight junction protein in Sertoli cells.24 Disruption of this process halts spermatogenesis.
Phosphodiesterase-5 inhibitors
Phosphodiesterase-5 (PDE5) inhibitors increase intracellular cyclic guanosine monophosphate, causing nitric oxide-mediated relaxation of smooth muscle throughout the prostate, detrusor muscle (bladder), and urethra.27 It is thought that this is the beneficial mechanism of action of PDE5 inhibitors on patients with BPH and lower urinary tract symptoms. Tadalafil is the most-studied PDE5 inhibitor for patients with BPH and lower urinary tract symptoms, with an average improvement in International Prostate Symptom Score of 3 or more. The onset of effect is variable but usually within hours. Importantly, avanafil has the shortest onset of action (15–20 minutes) in this class but is not widely used for the treatment of BPH.5,28
Side effects of PDE5 inhibitors include facial flushing, headache, back pain, dyspepsia, and the potential for blue-tinted vision; however, most of these side effects are minimal or absent at low daily doses for BPH. Well-known contraindications to PDE5 inhibitors include the use of nitrates.5,14
Beta-3 agonists and anticholinergics
Beta-3 agonists, including mirabegron and vibegron, work via the sympathetic pathway to cause relaxation of the detrusor muscle and increase bladder capacity.5,14They are indicated for patients with overactive bladder and can benefit patients with predominantly irritative lower urinary tract symptoms, including urgency, frequency, and incontinence. The onset of maximum effect is generally at around 3 weeks, an important factor to discuss with patients. While vibegron is only available in 1 dose, mirabegron is available in multiple doses and seems to provide similar therapeutic benefits 32 Emerging research suggests this class of drugs may also benefit patients with BPH, but this remains an area of active investigation.33
Historically and prior to beta-3 agonist development, anticholinergic medications were used to treat bothersome symptoms. Currently, they are widely available, and many are generic. However, anticholinergic medications are associated with cognitive impairment and dementia, in addition to the wellknown side effects of mental fogginess or confusion. 14 Studies have shown that trospium, a larger quaternaryamine molecule, does not cross the blood-brain barrier and may be a safer option.32
However, all anticholinergics have undesired side effects, including dry mouth, dry eyes, constipation, and potential vision changes.14 Anticholinergics exert therapeutic effect within hours to days, although this can vary between short- and long-acting formulations, as well as different doses (as anticholinergics can be titrated up for efficacy). Long-acting formulations tend to have less bothersome side effects, as these agents do not achieve the high peak serum levels responsible for unwanted effects.5,14
In contrast, beta-3 agonists have very favorable side-effect profiles and little to no risk for those with dementia or cognitive impairment.32–34 The most common side effect of mirabegron is hypertension. Due to the risk of drug-drug interaction, concomitant use of patients on metoprolol must be done cautiously.35 Overall, both mirabegron and vibegron are contraindicated in patients with poorly controlled hypertension, although vibegron has been found clinically to pose a negligible risk of blood pressure change. As a relatively newer therapeutic class, much remains to be learned about beta-3 agonists, but the initial clinical experience with them has been promising.32–34 Additionally, beta-3 antagonists can be combined with anticholinergics for the treatment of severe overactive bladder, as both agents target the bladder through 2 separate and synergistic molecular pathways.5
Combination therapy
Combination pharmacotherapy has been shown to be more effective than monotherapy or placebo, specifically in patients with larger prostates who meet the criteria for 5ARIs and can be offered alpha-blockers simultaneously.15,17,36 6 This follows findings from the 2003 MTOPS (Medical Therapy of Prostatic Symptoms) study of combination doxazosin and finasteride vs monotherapy or placebo that demonstrated decreased rates of symptom progression, urinary retention, and invasive BPH surgery or procedures with combination therapy.15,37 Similarly, the 2010 CombAT (Combination of Avodart and Tamsulosin) trial found a significant reduction in the relative risk of primary endpoints of acute urinary retention or prostatic hyperplasia-related surgery with combined tamsulosin and dutasteride compared with monotherapy (P < .001).36 There is growing evidence that daily tadalafil and fi finasteride combination is also helpful, with the added benefit t of avoiding alpha-blocker side effects.13,38
Historically, anticholinergic agents were offered in combination with an alpha-blocker for patients experiencing predominantly irritative lower urinary tract symptoms. However, studies have demonstrated variable improvements in the International ProstateSymptom Score for this combination compared with monotherapy.5 As a result, and considering the potential cognitive effects of anticholinergics, this warrants careful consideration. However, in this same population, combining alpha-blockers with beta-3 agonists presents a safer and well-tolerated alternative to improved symptoms with fewer side effects.5 Lastly, while many drug interaction systems may warn against concomitant use of PDE5 inhibitors and alpha-blockers, this combination remains an option for some, albeit with close monitoring as it can lead to symptomatic orthostatic hypotension.17,27
■ MEDICINAL PLANTS
Medicinal plants and natural products derived from plants are becoming more common for the treatment of BPH with lower urinary tract symptoms.34,39,40 Knowing the common medicinal plants targeted for patients with lower urinary tract symptoms from BPH and how to counsel regarding them are essential. Pumpkin seed (Cucurbita pepo) or its extract is popular and contains a variety of biologically active compounds thought to inhibit 5-alpha reductase and decrease levels of circulating dihydrotestosterone.22 However, pumpkin can cause gastrointestinal symptoms such as indigestion and diarrhea. Another common supplement is the fruit extract of the saw palmetto plant (Serenoa repens), which is sold over the counter. Postulated mechanisms of action for Serenoa repens include 5-alpha reductase inhibition and inhibition of dihydrotestosterone binding to androgen receptors.22,24,25 However, there have been mixed results regarding the exact mechanism of action of each of these supplements, and the results vary further based on the method of extraction and formulation.
Patients should be informed that many studies on supplements, nutraceuticals, and herbal preparations are limited by a lack of peer review, comparison with placebo control, and assessment using conventional endpoints.5 The 2 independently conducted, placebo-controlled trials using specific extracts of saw palmetto found no benefit over placebo across multiple measurable parameters relevant to BPH and lower urinary tract symptoms.41,42
Additionally, as regulation and quality control of natural products derived from plants are not as stringent as those of the pharmaceutical industry, it is important to educate patients that the composition of certain supplements varies not only between retailers but also between batches of supplements made by an individual manufacturer.34 As a result, their effect, if any, can vary widely and be unpredictable. Additionally, manufacturers of natural products derived from plants often post claims regarding efficacy and effects that are not regulated or endorsed by the US Food and Drug Administration.
■ CONCLUSION
Several options exist for the medical management of BPH, and choices are affected by indication, effectiveness, and side effects (Figure 1).7 Research continues regarding new agents and natural products derived from plants. While medication is a therapeutic option, it can provide diagnostic insight into the potential benefit of a procedure or surgery for patients with BPH. Furthermore, contemporary clinical management of BPH includes the consideration of surgeries or procedures as viable first-line options for properly selected, treatment-naïve patients, especially with the growing number of newer minimally invasive procedures with favorable side effects
In line with this, some patients may wish to avoid the side effects of medications, taking a daily pill, or the cost burden of lifelong pharmacotherapy. Others may experience disease progression in spite of medical treatment. Beyond these reasons, as well as medication intolerance or allergy, the American Urological Association guidelines list the following indications for patients with BPH to undergo procedures or surgeries: urinary retention, recurrent urinary tract infections, bladder stones, obstructive uropathy, and prostate-related hematuria.5 However, as noted earlier, contemporary approaches to the management of BPH emphasize patient preference as a major factor for determining whether to pursue medical, procedural, or surgical treatment. The growing list of surgical and procedural treatment options for BPH is covered in another review.43
Medical management of benign prostatic hyperplasia(BPH) has progressed gradually in recent years and remains the starting point for most symptomatic patients seeking treatment. Beyond well-known alpha-blockers and 5-alpha reductase inhibitors, there is growing evidence for the use of phosphodiesterase-5 inhibitors and beta-3 agonists in managing the condition, which may afford additional relief of “bothersome” symptoms in some patients. This review details the contemporary medical management of BPH with an emphasis on the indications for certain classes of pharmacotherapy and their relative benefits ts and side effects. Surgical and procedural treatment of BPH is covered in a separate review.
Benign prostatic hyperplasia (BPH), also known as benign prostate enlargement or obstruction, is a histologic diagnosis that describes the proliferation of glandular epithelial tissue and smooth muscle within the transition zone of the prostate.1,2 The prostate gland has both intrinsic and extrinsic factors that likely play complex roles in its growth. These include the interaction between the stroma and epithelium, hormone and androgen exposure (specifically testosterone and, more importantly, dihydrotestosterone), dietary factors, micro-organisms, and genetic predisposition.1,2
Although the exact mechanism for the development of BPH is unknown, age-related changes causing metabolic disturbances, changes in hormone balance, and chronic inflammation appear to contribute.3 Despite diminishing levels of testosterone as patients grow older, the amount of circulating dihydrotestosterone and prostatic androgen receptors remains high.2 The average prostate is approximately 20 cc between the ages of 21 and 30.BPH can begin to develop in the early 40s in some men and is found in 50% of men ages 51 to 60.3,4 The prevalence of BPH increases steadily with age, reaching 60% at age 60 and 80% at age 80.5 An enlarged prostate gland, while not in itself pathologic, can result in lower urinary tract symptoms, either by directly obstructing the bladder outlet as enlargement changes the shape of the gland or by increasing smooth muscle tone and resistance to flow within the enlarged gland.2
Lower urinary tract symptoms associated with BPH are characterized as disturbances in the retention of urine, voiding, and postmicturition state. These symptoms provide insight into the impact of BPH on patient quality of life.6,7 The International Prostate Symptom Score is a validated 8-point questionnaire that numerically characterizes patient symptoms.8–10 Three questions pertain to storage symptoms (frequency, nocturia, urgency), and 4 pertain to voiding (feelings of incomplete emptying, weak stream, intermittency, straining). The final question assesses the self-reported impact of symptoms on patient quality of life
The goal of treatment for lower urinary tract symptoms associated with BPH has long been to maximize quality of life and minimize “bothersome” symptoms. More recently, the focus on preventing side effects or treatment complications has been growing. This review outlines the most common medical treatments for lower urinary tract symptoms associated with benign prostatic hyperplasia.
■ DIAGNOSTIC EVALUATION
■ CONSERVATIVE MANAGEMENT
■ PHARMACOTHERAPY
Alpha-blockers
Alpha-blockers are a class of drugs first introduced in the late 1980s and early 1990s. They work by antagonizing alpha-1 receptors in the bladder neck and prostate, which results in the relaxation of smooth muscle in these areas,12–17 and in turn, reduced constriction of the urinary channel and lower resistance to urinary flow. 14 Despite a plethora of medications within this class, all are relatively equally effective, with an expected international Prostate Symptom Score improvement from a baseline of 3.7 to 7.1 points.13
The 5 main alpha-blocker medications include second-generation drugs (terazosin, doxazosin) and third-generation drugs (tamsulosin, alfuzosin, silodosin). The third-generation drugs are generally well-tolerated, and tamsulosin is associated with fewer side effects.12 The second-generation alpha-blocker medications require dose titration owing to their antihypertensive effects.12
The therapeutic effect of alpha-blockers starts within hours to days, although it generally takes 3 to 7 days to reach maximum effect.13–15,18 Common side effects include lightheadedness, dizziness, headache, nasal congestion, erectile dysfunction, and ejaculatory dysfunction or anejaculation (formerly known as retrograde ejaculation). These side effects usually accompany the therapeutic effect of the medication, are generally dose-dependent, and resolve within a few days with medication discontinuation. Ejaculatory dysfunction results from the relaxation of the smooth muscle within the prostatic and ejaculatory ducts with alpha blockade.19 This can be very distressing and bothersome for some and a relevant clinical concern for men who may want to father a child, as they may be unable to do so while using alpha-blockers.
5-alpha reductase inhibitors
Androgens are essential to prostatic growth.16 The conversion of testosterone to dihydrotestosterone, a more potent ligand for the androgen receptor and arbiter of prostatic growth is central to this process.14–17,22 Inhibiting the conversion of testosterone to dihydrotestosterone with 5-alpha reductase inhibitors(5ARIs) can reduce prostate growth and tip the scales toward prostatic cellular apoptosis and atrophy. Atrophy is more pronounced in the glandular epithelium of the prostate where PSA is made, as opposed to the smooth muscle stromal component of the gland. 23 Thus, gland composition (more glandular vs more stromal) may impact medication efficacy. The impact of 5ARIs on the glandular cells results in a decrease in PSA of approximately 50% after 6 to 12 months of treatment.16,22,23 Therefore, because PSA is a key predictor of treatment outcome, measurement of baseline PSA is recommended for all patients considering 5ARI therapy.
Owing to their mechanism of action and effect on gland size, 5ARIs should be reserved for patients with BPH and lower urinary tract symptoms who have prostate glands 30 cc or larger or palpable prostatic enlargement on digital rectal examination.16,23 Finasteride and dutasteride are the most commonly used 5ARIs.16,22,23 Finasteride inhibits the 5AR type II isoenzyme, while dutasteride inhibits type I and II isoenzymes.22 Because type II 5AR is more commonly found in prostate tissue, the clinical effect of these medications does not differ. Notably, 5ARIs require about 3 months of use before noticeable improvements in urinary symptoms occur, and approximately 6 months to reach full effect in terms of prostate volume reduction.16,22,23 It is critically important to explain to patients the expected timeframe to ensure medication adherence.
5ARIs for prostate cancer prevention have been studied for some time, with the evidence showing these medications reduce overall prostate cancer rates, particularly low-grade cancers. This is likely because fi finasteride reduces prostate volume, resulting in improved detection of cancer on prostate biopsy, and because of its selective inhibition of low-grade cancers.16,22 There is a black box warning regarding 5ARIs because they were thought to potentially increase the risk for higher-grade prostate cancers, but were later determined to be helpful in the process of detecting these cancers.5,16,22 These medications are regularly used and thought to be safe.
Side effects of 5ARIs vary widely across research studies but include bothersome symptoms related to testosterone deficiency including erectile dysfunction, ejaculatory dysfunction (reduced semen volume and thinned semen consistency), decreased libido, and possible fertility implications.5,24 Although a causal link between 5ARIs and infertility has yet to be elucidated, the 5-alpha reductase is physiologically active in human testes, with dihydrotestosterone promoting the expression of tight junction protein in Sertoli cells.24 Disruption of this process halts spermatogenesis.
Phosphodiesterase-5 inhibitors
Phosphodiesterase-5 (PDE5) inhibitors increase intracellular cyclic guanosine monophosphate, causing nitric oxide-mediated relaxation of smooth muscle throughout the prostate, detrusor muscle (bladder), and urethra.27 It is thought that this is the beneficial mechanism of action of PDE5 inhibitors on patients with BPH and lower urinary tract symptoms. Tadalafil is the most-studied PDE5 inhibitor for patients with BPH and lower urinary tract symptoms, with an average improvement in International Prostate Symptom Score of 3 or more. The onset of effect is variable but usually within hours. Importantly, avanafil has the shortest onset of action (15–20 minutes) in this class but is not widely used for the treatment of BPH.5,28
Side effects of PDE5 inhibitors include facial flushing, headache, back pain, dyspepsia, and the potential for blue-tinted vision; however, most of these side effects are minimal or absent at low daily doses for BPH. Well-known contraindications to PDE5 inhibitors include the use of nitrates.5,14
Beta-3 agonists and anticholinergics
Beta-3 agonists, including mirabegron and vibegron, work via the sympathetic pathway to cause relaxation of the detrusor muscle and increase bladder capacity.5,14They are indicated for patients with overactive bladder and can benefit patients with predominantly irritative lower urinary tract symptoms, including urgency, frequency, and incontinence. The onset of maximum effect is generally at around 3 weeks, an important factor to discuss with patients. While vibegron is only available in 1 dose, mirabegron is available in multiple doses and seems to provide similar therapeutic benefits 32 Emerging research suggests this class of drugs may also benefit patients with BPH, but this remains an area of active investigation.33
Historically and prior to beta-3 agonist development, anticholinergic medications were used to treat bothersome symptoms. Currently, they are widely available, and many are generic. However, anticholinergic medications are associated with cognitive impairment and dementia, in addition to the wellknown side effects of mental fogginess or confusion. 14 Studies have shown that trospium, a larger quaternaryamine molecule, does not cross the blood-brain barrier and may be a safer option.32
However, all anticholinergics have undesired side effects, including dry mouth, dry eyes, constipation, and potential vision changes.14 Anticholinergics exert therapeutic effect within hours to days, although this can vary between short- and long-acting formulations, as well as different doses (as anticholinergics can be titrated up for efficacy). Long-acting formulations tend to have less bothersome side effects, as these agents do not achieve the high peak serum levels responsible for unwanted effects.5,14
In contrast, beta-3 agonists have very favorable side-effect profiles and little to no risk for those with dementia or cognitive impairment.32–34 The most common side effect of mirabegron is hypertension. Due to the risk of drug-drug interaction, concomitant use of patients on metoprolol must be done cautiously.35 Overall, both mirabegron and vibegron are contraindicated in patients with poorly controlled hypertension, although vibegron has been found clinically to pose a negligible risk of blood pressure change. As a relatively newer therapeutic class, much remains to be learned about beta-3 agonists, but the initial clinical experience with them has been promising.32–34 Additionally, beta-3 antagonists can be combined with anticholinergics for the treatment of severe overactive bladder, as both agents target the bladder through 2 separate and synergistic molecular pathways.5
Combination therapy
Combination pharmacotherapy has been shown to be more effective than monotherapy or placebo, specifically in patients with larger prostates who meet the criteria for 5ARIs and can be offered alpha-blockers simultaneously.15,17,36 6 This follows findings from the 2003 MTOPS (Medical Therapy of Prostatic Symptoms) study of combination doxazosin and finasteride vs monotherapy or placebo that demonstrated decreased rates of symptom progression, urinary retention, and invasive BPH surgery or procedures with combination therapy.15,37 Similarly, the 2010 CombAT (Combination of Avodart and Tamsulosin) trial found a significant reduction in the relative risk of primary endpoints of acute urinary retention or prostatic hyperplasia-related surgery with combined tamsulosin and dutasteride compared with monotherapy (P < .001).36 There is growing evidence that daily tadalafil and fi finasteride combination is also helpful, with the added benefit t of avoiding alpha-blocker side effects.13,38
Historically, anticholinergic agents were offered in combination with an alpha-blocker for patients experiencing predominantly irritative lower urinary tract symptoms. However, studies have demonstrated variable improvements in the International ProstateSymptom Score for this combination compared with monotherapy.5 As a result, and considering the potential cognitive effects of anticholinergics, this warrants careful consideration. However, in this same population, combining alpha-blockers with beta-3 agonists presents a safer and well-tolerated alternative to improved symptoms with fewer side effects.5 Lastly, while many drug interaction systems may warn against concomitant use of PDE5 inhibitors and alpha-blockers, this combination remains an option for some, albeit with close monitoring as it can lead to symptomatic orthostatic hypotension.17,27
■ MEDICINAL PLANTS
Medicinal plants and natural products derived from plants are becoming more common for the treatment of BPH with lower urinary tract symptoms.34,39,40 Knowing the common medicinal plants targeted for patients with lower urinary tract symptoms from BPH and how to counsel regarding them are essential. Pumpkin seed (Cucurbita pepo) or its extract is popular and contains a variety of biologically active compounds thought to inhibit 5-alpha reductase and decrease levels of circulating dihydrotestosterone.22 However, pumpkin can cause gastrointestinal symptoms such as indigestion and diarrhea. Another common supplement is the fruit extract of the saw palmetto plant (Serenoa repens), which is sold over the counter. Postulated mechanisms of action for Serenoa repens include 5-alpha reductase inhibition and inhibition of dihydrotestosterone binding to androgen receptors.22,24,25 However, there have been mixed results regarding the exact mechanism of action of each of these supplements, and the results vary further based on the method of extraction and formulation.
Patients should be informed that many studies on supplements, nutraceuticals, and herbal preparations are limited by a lack of peer review, comparison with placebo control, and assessment using conventional endpoints.5 The 2 independently conducted, placebo-controlled trials using specific extracts of saw palmetto found no benefit over placebo across multiple measurable parameters relevant to BPH and lower urinary tract symptoms.41,42
Additionally, as regulation and quality control of natural products derived from plants are not as stringent as those of the pharmaceutical industry, it is important to educate patients that the composition of certain supplements varies not only between retailers but also between batches of supplements made by an individual manufacturer.34 As a result, their effect, if any, can vary widely and be unpredictable. Additionally, manufacturers of natural products derived from plants often post claims regarding efficacy and effects that are not regulated or endorsed by the US Food and Drug Administration.
■ CONCLUSION
Several options exist for the medical management of BPH, and choices are affected by indication, effectiveness, and side effects (Figure 1).7 Research continues regarding new agents and natural products derived from plants. While medication is a therapeutic option, it can provide diagnostic insight into the potential benefit of a procedure or surgery for patients with BPH. Furthermore, contemporary clinical management of BPH includes the consideration of surgeries or procedures as viable first-line options for properly selected, treatment-naïve patients, especially with the growing number of newer minimally invasive procedures with favorable side effects
In line with this, some patients may wish to avoid the side effects of medications, taking a daily pill, or the cost burden of lifelong pharmacotherapy. Others may experience disease progression in spite of medical treatment. Beyond these reasons, as well as medication intolerance or allergy, the American Urological Association guidelines list the following indications for patients with BPH to undergo procedures or surgeries: urinary retention, recurrent urinary tract infections, bladder stones, obstructive uropathy, and prostate-related hematuria.5 However, as noted earlier, contemporary approaches to the management of BPH emphasize patient preference as a major factor for determining whether to pursue medical, procedural, or surgical treatment. The growing list of surgical and procedural treatment options for BPH is covered in another review.43
