Approach Considerations
Patients with mild symptoms (IPSS/AUA-SI score < 7) or moderate-to-severe symptoms (IPSS/AUA-SI score ≥8) of benign prostatic hyperplasia (BPH) who are not bothered by their symptoms and are not experiencing complications of BPH should be managed with a strategy of watchful waiting. In these situations, medical therapy is not likely to improve their symptoms and/or quality of life (QOL). In addition, the risks of treatment may outweigh any benefits. Patients managed expectantly with watchful waiting are usually re-examined annually.
Transurethral resection of the prostate (TURP) has long been accepted as the criterion standard for relieving bladder outlet obstruction (BOO) secondary to BPH. In current clinical practice, most patients with BPH do not present with obvious surgical indications; instead, they often have milder lower urinary tract symptoms (LUTS) and, therefore, are initially treated with medical therapy.
The era of medical therapy for BPH dawned in the mid 1970s with the use of nonselective alpha-blockers such as phenoxybenzamine. The medical therapeutic options for BPH have evolved significantly over the last 3 decades, giving rise to the receptor-specific alpha-blockers that comprise the first line of therapy.
BPH is predominantly a stromal proliferative process, and a significant component of prostatic enlargement results from smooth-muscle proliferation. The stromal-to-epithelial ratio is significantly greater in men with symptomatic BPH than in those with asymptomatic BPH.
The 3 subtypes of the alpha-1 receptor include 1a, 1b, and 1c. Of these, the alpha-1a receptor is most specifically concentrated in the bladder neck and prostate. Provided that the alpha-1a subtype is predominant in the prostate, bladder neck, and urethra, but not in other tissues, drugs that are selective for this receptor (ie, tamsulosin) may have a potential therapeutic advantage.
Tamsulosin is considered the most pharmacologically uroselective of the commercially available agents because of its highest relative affinity for the alpha-1a receptor subtype. In 2008, the US Food and Drug Administration (FDA) approved a new alpha-1a receptor selective blocker, silodosin (Rapaflo). It is indicated for treatment of the signs and symptoms of BPH.
The efficacy of the titratable alpha-blockers doxazosin and terazosin (Hytrin) is dose-dependent. Maximum tolerable doses have not been defined for any alpha-blocker; however, the higher the dose, the more likely the adverse events (orthostatic hypotension, dizziness, fatigue, ejaculatory disorder, nasal congestion). Despite the requirement for dose titration and blood pressure monitoring, these older, often less costly, alpha-blockers appear to be equally effective to tamsulosin and alfuzosin, and the 2010 AUA guidelines state that they remain reasonable choices for patients with moderate-to-severe LUTS due to BPH.[2]
An approximately 4- to 6-point improvement is expected in IPSS/AUA-SI scores when alpha-blockers are used. Interestingly, alpha-blocker therapy has not been shown to reduce the overall long-term risk for acute urinary retention (AUR) or BPH-related surgery.[7]
Hellstrom and Sikka reported in 2006 that the acute administration of tamsulosin effects ejaculatory function and ejaculate volume. Nearly 90% of study subjects experienced decreased ejaculate volume, and approximately 35% experienced anejaculation. In their study, subjects treated with alfuzosin or placebo did not experience anejaculation.[8]
In a review by Bell et al, exposure to tamsulosin within 14 days of cataract surgery was significantly associated with serious postoperative ophthalmic adverse events, specifically IFIS and its complications (ie, retinal detachment, lost lens or fragments, endophthalmitis). No significant associations were noted with exposure to other alpha-blocker medications or to previous exposure to tamsulosin or other alpha-blockers.[10]
Inhibition of 5-alpha-reductase type 2 blocks the conversion of testosterone to DHT, resulting in lower intraprostatic levels of DHT. This leads to inhibition of prostatic growth, apoptosis, and involution. The exact role of 5-alpha-reductase type 1 in normal and abnormal prostatic development is undefined. 5-Alpha-reductase inhibitors improve LUTS by decreasing prostate volumes; thus, patients with larger prostates may achieve a greater benefit. Further, maximal reduction in prostate volume requires 6 months of therapy.
Dutasteride (Avodart) has an affinity for both type 1 and type 2 5-alpha-reductase receptors. The significance of blockage of type 1 receptors is currently unknown.
Both finasteride and dutasteride actively reduce DHT levels by more than 80%, improve symptoms, reduce the incidence of urinary retention, and decrease the likelihood of surgery for BPH. Adverse effects are primarily sexual in nature (decreased libido, erectile dysfunction, ejaculation disorder).
Both finasteride and dutasteride may reduce serum prostate-specific antigen (PSA) values by as much as 50%. The decrease in PSA is typically maximally achieved when the maximal decrease in prostatic volume is noted (6 months). Thus, one must take this into account when using PSA to screen for prostate cancer.
One prospective, randomized, double-blind study by the Enlarged Prostate International Comparator Study (EPICS) was conducted to compare the efficacy of dutasteride to that of finasteride in men with symptomatic BPH. While this study was conducted over the course of only one year, the data suggest that both of these drugs were similarly effective in reducing prostate volume, improving Qmax, and LUTS for this population. The long-term outcomes are yet to be investigated.[11]
Because these drugs interfere with the metabolism of testosterone, they are contraindicated in children and pregnant females. In addition, pregnant females or those who are considering conception should not handle crushed or broken tablets because of the potential for absorption and subsequent potential risk to a male fetus.
In patients with LUTS and enlarged prostates, 5-alpha-reductase inhibitors are believed to be appropriate and effective treatment.
Data from 2 large, randomized, controlled trials observed an increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer) in trial participants taking 5-ARIs. The 2 trials are the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. Both of these trials observed a decreased incidence of prostate cancer overall when preventive treatment included 5-ARIs, but an increased incidence of high-grade prostate cancer in men taking dutasteride or finasteride compared with placebo.[12, 13]
The revised prescribing information recommends that prior to initiating therapy with 5-ARIs, perform appropriate evaluations to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH).
Transurethral resection of the prostate (TURP) has long been accepted as the criterion standard for relieving bladder outlet obstruction (BOO) secondary to BPH. In current clinical practice, most patients with BPH do not present with obvious surgical indications; instead, they often have milder lower urinary tract symptoms (LUTS) and, therefore, are initially treated with medical therapy.
The era of medical therapy for BPH dawned in the mid 1970s with the use of nonselective alpha-blockers such as phenoxybenzamine. The medical therapeutic options for BPH have evolved significantly over the last 3 decades, giving rise to the receptor-specific alpha-blockers that comprise the first line of therapy.
Alpha-1–Receptor Blockade in Benign Prostatic Hyperplasia
A significant component of LUTS secondary to BPH is believed to be related to the smooth-muscle tension in the prostate stroma, urethra, and bladder neck. The smooth-muscle tension is mediated by the alpha-1-adrenergic receptors; therefore, alpha-adrenergic receptor–blocking agents should theoretically decrease resistance along the bladder neck, prostate, and urethra by relaxing the smooth muscle and allowing passage of urine.BPH is predominantly a stromal proliferative process, and a significant component of prostatic enlargement results from smooth-muscle proliferation. The stromal-to-epithelial ratio is significantly greater in men with symptomatic BPH than in those with asymptomatic BPH.
The 3 subtypes of the alpha-1 receptor include 1a, 1b, and 1c. Of these, the alpha-1a receptor is most specifically concentrated in the bladder neck and prostate. Provided that the alpha-1a subtype is predominant in the prostate, bladder neck, and urethra, but not in other tissues, drugs that are selective for this receptor (ie, tamsulosin) may have a potential therapeutic advantage.
Tamsulosin is considered the most pharmacologically uroselective of the commercially available agents because of its highest relative affinity for the alpha-1a receptor subtype. In 2008, the US Food and Drug Administration (FDA) approved a new alpha-1a receptor selective blocker, silodosin (Rapaflo). It is indicated for treatment of the signs and symptoms of BPH.
The efficacy of the titratable alpha-blockers doxazosin and terazosin (Hytrin) is dose-dependent. Maximum tolerable doses have not been defined for any alpha-blocker; however, the higher the dose, the more likely the adverse events (orthostatic hypotension, dizziness, fatigue, ejaculatory disorder, nasal congestion). Despite the requirement for dose titration and blood pressure monitoring, these older, often less costly, alpha-blockers appear to be equally effective to tamsulosin and alfuzosin, and the 2010 AUA guidelines state that they remain reasonable choices for patients with moderate-to-severe LUTS due to BPH.[2]
An approximately 4- to 6-point improvement is expected in IPSS/AUA-SI scores when alpha-blockers are used. Interestingly, alpha-blocker therapy has not been shown to reduce the overall long-term risk for acute urinary retention (AUR) or BPH-related surgery.[7]
Hellstrom and Sikka reported in 2006 that the acute administration of tamsulosin effects ejaculatory function and ejaculate volume. Nearly 90% of study subjects experienced decreased ejaculate volume, and approximately 35% experienced anejaculation. In their study, subjects treated with alfuzosin or placebo did not experience anejaculation.[8]
Alpha-adrenergic receptor blockers
The alpha-blocking agents administered in BPH studies can be subgrouped according to receptor subtype selectivity and the duration of serum elimination half-lives, as follows:- Nonselective alpha-blockers - phenoxybenzamine
- Selective short-acting alpha-1 blockers - prazosin, alfuzosin, indoramin
- Selective long-acting alpha-1 blockers - terazosin, doxazosin, slow-release (SR) alfuzosin.
- Partially subtype (alpha-1a)–selective agents – tamsulosin, silodosin
Nonselective alpha-blockers
Phenoxybenzamine was the first alpha-blocker studied for BPH. It is nonselective, antagonizing both the alpha 1- and alpha 2-adrenergic receptors, which results in a higher incidence of adverse effects. Because of the availability of more alpha-1-receptor–specific agents, phenoxybenzamine is currently not often used for the treatment of BPH. The 2010 update to the AUA guideline for BPH retains the statement that insufficient data exist for a recommendation of phenoxybenzamine or of prazosin for treatment of LUTS secondary to BPH. This statement was originally published in the 2003 AUA BPH guidelines.[2]Phosphodiesterase-5 enzyme inhibitors
Statistically significant symptomatic improvements have been reported for patients with BPH receiving tadalafil. It has also been approved for the treatment of simultaneous BPH and erectile dysfunction (ED). Phosphdiesterase-5 (PDE5) inhibitors are known to mediate smooth muscle relaxation in the lower urinary tract.Intraoperative floppy iris syndrome
Intraoperative floppy iris syndrome (IFIS) is characterized by miosis, iris billowing, and prolapse in patients undergoing cataract surgery who have taken or currently take alpha-1-blockers. It is particularly prevalent among patients taking tamsulosin. The 2010 AUA guideline recommends that clinicians ask patients about planned cataract surgery when offering alpha-blocker therapy for LUTS due to BPH. Alpha-blockers should not be initiated until cataract surgery is completed.[2] Patients currently on alpha-blocker therapy must disclose this to their ophthalmologist prior to cataract surgery so that the appropriate preoperative and intraoperative precautions can be taken. Experienced ophthalmologists can thereby reduce the risk of complications from IFIS.[9, 2]In a review by Bell et al, exposure to tamsulosin within 14 days of cataract surgery was significantly associated with serious postoperative ophthalmic adverse events, specifically IFIS and its complications (ie, retinal detachment, lost lens or fragments, endophthalmitis). No significant associations were noted with exposure to other alpha-blocker medications or to previous exposure to tamsulosin or other alpha-blockers.[10]
5-Alpha-Reductase Inhibitors in Benign Prostatic Hyperplasia
Hormonal medical management emerged from the discovery of a congenital form of pseudohermaphroditism secondary to DHT deficiency (due to a lack of 5-alpha-reductase activity). This deficiency produced a hypoplastic prostate. The two types of 5-alpha-reductase include type 1 (predominantly located in extraprostatic tissues, such as skin and liver) and type 2 (predominant prostatic reductase).Inhibition of 5-alpha-reductase type 2 blocks the conversion of testosterone to DHT, resulting in lower intraprostatic levels of DHT. This leads to inhibition of prostatic growth, apoptosis, and involution. The exact role of 5-alpha-reductase type 1 in normal and abnormal prostatic development is undefined. 5-Alpha-reductase inhibitors improve LUTS by decreasing prostate volumes; thus, patients with larger prostates may achieve a greater benefit. Further, maximal reduction in prostate volume requires 6 months of therapy.
5-Alpha reductase inhibitors
Finasteride (Proscar), a 4-aza-steroid, has demonstrated 5-alpha type II–blocking activity, resulting in the inhibition of DHT-receptor complex formation. This effect causes a profound decrease in the concentration of DHT intraprostatically, resulting in a consistent decrease in prostate size. One third of men treated with this agent exhibit improvements in urine flow and symptoms.Dutasteride (Avodart) has an affinity for both type 1 and type 2 5-alpha-reductase receptors. The significance of blockage of type 1 receptors is currently unknown.
Both finasteride and dutasteride actively reduce DHT levels by more than 80%, improve symptoms, reduce the incidence of urinary retention, and decrease the likelihood of surgery for BPH. Adverse effects are primarily sexual in nature (decreased libido, erectile dysfunction, ejaculation disorder).
Both finasteride and dutasteride may reduce serum prostate-specific antigen (PSA) values by as much as 50%. The decrease in PSA is typically maximally achieved when the maximal decrease in prostatic volume is noted (6 months). Thus, one must take this into account when using PSA to screen for prostate cancer.
One prospective, randomized, double-blind study by the Enlarged Prostate International Comparator Study (EPICS) was conducted to compare the efficacy of dutasteride to that of finasteride in men with symptomatic BPH. While this study was conducted over the course of only one year, the data suggest that both of these drugs were similarly effective in reducing prostate volume, improving Qmax, and LUTS for this population. The long-term outcomes are yet to be investigated.[11]
Because these drugs interfere with the metabolism of testosterone, they are contraindicated in children and pregnant females. In addition, pregnant females or those who are considering conception should not handle crushed or broken tablets because of the potential for absorption and subsequent potential risk to a male fetus.
In patients with LUTS and enlarged prostates, 5-alpha-reductase inhibitors are believed to be appropriate and effective treatment.
5-Alpha reductase inhibitors and prostate cancer
On June 9, 2011, the US Food and Drug Administration announced revisions to the prescribing information for 5-alpha reductase inhibitors (5-ARIs). These agents include finasteride (Proscar, Propecia) and dutasteride (Avodart, Jalyn). 5-ARIs are indicated for benign prostatic hypertrophy and alopecia.Data from 2 large, randomized, controlled trials observed an increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer) in trial participants taking 5-ARIs. The 2 trials are the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. Both of these trials observed a decreased incidence of prostate cancer overall when preventive treatment included 5-ARIs, but an increased incidence of high-grade prostate cancer in men taking dutasteride or finasteride compared with placebo.[12, 13]
The revised prescribing information recommends that prior to initiating therapy with 5-ARIs, perform appropriate evaluations to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH).
Combination Therapy
The alpha-1-receptor blockers provide rapid relief, while the 5-alpha-reductase inhibitors target the underlying disease process.[7] The Medical Therapy of Prostatic Symptoms (MTOPS) trial demonstrated that combination therapy reduced the risk of progression and produced a greater improvement in IPSS than therapy with finasteride or doxazosin alone. The risks of AUR and BPH-related surgery were reduced with combination therapy or finasteride in comparison with doxazosin monotherapy.[14]
The Symptom Management After Reducing Therapy (SMART-1) trial demonstrated that after 6 months of combination therapy, discontinuation of the alpha-1-blocker is possible in men with moderate LUTS. However, those with severe LUTS may require longer combination therapy.[14]
The 2010 AUA BPH guidelines recommend anticholinergic agents for management of LUTS in patients who do not have an elevated PVR and whose LUTS are primarily irritative. Baseline PVR should be obtained prior to initiation of anticholinergic therapy, to assess for urinary retention.[15] Caution with anticholinergics is recommended with patients whose PVR is greater than 250-300 mL.[2]
The Proscar Long-Term Efficacy and Safety Study (PLESS), patients treated with finasteride (5 mg/d) were at a significantly lower risk of developing AUR or needing surgery.[16] This was a multicenter, 4-year, double-blind, placebo-controlled study of 3,040 men. Men with PSA levels of more than 10 ng/mL and those with prostate cancer were excluded.
The Medical Therapy of Prostatic Symptoms (MTOPS) trial demonstrated that combination therapy with doxazosin and finasteride was well tolerated, and was superior to placebo and monotherapy with either agent. The primary endpoints of the study were reduction in AUA-SI score, AUR, recurrent infections, renal insufficiency, incontinence, changes in flow, and PSA level and a lower rate of invasive treatments. MTOPS was a multicenter, 4- to 6-year, double-blind, randomized, placebo-controlled trial of 3,047 men with symptomatic BPH.[17]
In the Alfuzosin Long-Term Efficacy and Safety Study (ALTESS), alfuzosin (10 mg/d) decreased the risk of LUTS deterioration and significantly improved QOL and peak urinary flow rate. ALTESS was a 2-year, double-blind, placebo-controlled study of 1,522 men. Notably, these men had greater risk factors for BPH progression (ie, older age, higher IPSS scores, larger prostate size, lower Qmax, and higher PVR) than those in the MTOPS trial. Alfuzosin did not reduce the risk of AUR but tended to reduce the risk of surgery.[18]
In the international real-life practice study of alfuzosin once daily (ALF-ONE), 3 years of alfuzosin (10 mg/d) decreased IPSS by one third, with significant improvements in nocturia and bother score. ALF-ONE was conducted in 689 European men with a mean age of 67.6 years. Clinical progression of worsening of IPSS (≥4 points) was seen in 12.4%, AUR in 2.6%, and requirement of BPH-related surgery in 5.7%. Alfuzosin was well tolerated, with dizziness the most common adverse effect (4.5%). Notably, symptom worsening during treatment and high PSA levels appeared to be the best predictors of clinical progression.[19]
Four-year results in the Combination of Avodart and Tamsulosin (CombAT) study revealed that for men with prostate volumes of 30-58 mL, combination therapy with dutasteride (dual 5-alpha-reductase inhibitor) and tamsulosin (alpha-1-blocker) improved symptoms, urinary flow, and QOL better than monotherapy with either drug, although not in men who had a prostate volume of 58 mL or more.[20] The adverse-effect profile of combination therapy was similar to that of monotherapy, although drug-related adverse events were more common with combination therapy.[21] CombAT is a 4-year, multicenter, randomized, double-blind, parallel group study of 4,844 men aged 50 years or older with moderate-to-severe BPH symptoms (IPSS ≥12), prostate volume of 30 mL or greater, and a PSA level of 1.5-10 ng/mL. This study contributes to the standard of care shifting towards combined drug therapy in appropriately selected patients, while better defining the role of the alpha-blockers.[15]
Pharmaceuticals derived from plant extracts are widely used throughout the world for the treatment of various medical ailments. In 1998, Americans spent a total of $3.65 billion on all herbal remedies. In France and Germany, plant extracts have a market share of up to 50% of all drugs prescribed for symptomatic BPH. In the United States, these agents are also popular and readily available.
The attraction to phytotherapeutic agents appears to be related to the perception of therapeutic healing powers of natural herbs, the ready availability, and the lack of adverse effects.
Most of the phytotherapeutic agents used in the treatment of LUTS secondary to BPH are extracted from the roots, seeds, bark, or fruits of plants listed below. Some suggested active components include phytosterols, fatty acids, lectins, flavonoids, plant oils, and polysaccharides. Some preparations derive from a single plant; others contain extracts from 2 or more sources.
Each agent has one or more proposed modes of action. The following modes of action are suggested:
The recommended dosage is 160 mg orally twice daily. Studies show significant subjective improvement in symptoms without objective improvements in urodynamic parameters. Minimal adverse effects include occasional GI discomfort.
The 2010 AUA guidelines, based on more recent studies, do not detect a clinically meaningful effect of saw palmetto on LUTS. Further clinical trials are underway.[2] In fact, in a double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites, saw palmetto extract was studied at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. Saw palmetto extract was no more effective than placebo on the American Urological Association Symptom Index. No clearly attributable adverse effects were identified. Similar to the Saw Palmetto Treatment for Enlarged Prostates (STEP) study, saw palmetto was not found to be beneficial for the treatment of LUTS in men.[22]
In addition to treating erectile dysfunction, sildenafil may improve mild-to-moderate LUTS. Nitric oxide may mediate relaxation of the prostatic urethra and/or bladder neck. The utility of phosphodiesterase inhibitors in the treatment of LUTS has yet to be defined.[26]
Recent trials have addressed the use of long-acting phosphodiesterase type 5 inhibitors (tadalafil) and have found them to be significantly better than placebo in improving the symptoms of BPH/LUTS.
TURP is performed with regional or general anesthesia and involves the placement of a working sheath in the urethra through which a hand-held device with an attached wire loop is placed. High-energy electrical cutting current is run through the loop so that the loop can be used to shave away prostatic tissue. The entire device is usually attached to a video camera to provide vision for the surgeon.
Although TURP is often successful, it has significant drawbacks. When prostatic tissue is cut away, significant bleeding may occur, possibly resulting in termination of the procedure, blood transfusion, and a prolonged hospital stay.
Irrigating fluid may also be absorbed in significant quantities through veins that are cut open, with possible serious sequelae termed transurethral resection syndrome (TUR syndrome). However, this is very rare and does not occur with saline irrigation used in bipolar devices. A urinary catheter must be left in place until the bleeding has mostly cleared.
The large working sheath combined with the use of electrical energy may also result in stricturing of the urethra.
The cutting of the prostate may also result in a partial resection of the urinary sphincteric mechanism, causing the muscle along the bladder outlet to become weak or incompetent. As a result, when the patient ejaculates, this sphincteric mechanism cannot keep the bladder adequately closed. The ejaculate consequently goes backwards into the bladder (ie, retrograde ejaculation), rather than out the penis. Additionally, if the urinary sphincter is damaged, urinary incontinence may result.
The nerves associated with erection run along the outer rim of the prostate, and the high-energy current and/or heat generated by such may damage these nerves, resulting in impotence.
TURP usually requires hospitalization.
Open prostatectomy requires hospitalization and involves the use of general/regional anesthesia and a lower abdominal incision. The inner core of the prostate (adenoma), which represents the transition zone, is shelled out, thus leaving the peripheral zone behind. This procedure may involve significant blood loss, resulting in transfusion. Open prostatectomy usually has an excellent outcome in terms of improvement of urinary flow and urinary symptoms.
More recently, laparoscopic simple prostatectomy has been performed at a number of institutions and appears to be feasible. However, prostatectomy performed in this fashion still appears to be associated with risk for significant blood loss. Experience to date with this procedure is limited.[27]
The Symptom Management After Reducing Therapy (SMART-1) trial demonstrated that after 6 months of combination therapy, discontinuation of the alpha-1-blocker is possible in men with moderate LUTS. However, those with severe LUTS may require longer combination therapy.[14]
Anticholinergic Agents
Historically, anticholinergics were discouraged in men with BPH because of concerns of inducing urinary retention. Trials have demonstrated a slight increase in PVR; however, AUR rates were low. Importantly, these trials consisted of patients with low baseline PVR.The 2010 AUA BPH guidelines recommend anticholinergic agents for management of LUTS in patients who do not have an elevated PVR and whose LUTS are primarily irritative. Baseline PVR should be obtained prior to initiation of anticholinergic therapy, to assess for urinary retention.[15] Caution with anticholinergics is recommended with patients whose PVR is greater than 250-300 mL.[2]
Landmark Clinical Trials
Numerous phase II and phase III trials of drugs used in the treatment of BPH have been conducted. A few landmark studies are selected below.The Proscar Long-Term Efficacy and Safety Study (PLESS), patients treated with finasteride (5 mg/d) were at a significantly lower risk of developing AUR or needing surgery.[16] This was a multicenter, 4-year, double-blind, placebo-controlled study of 3,040 men. Men with PSA levels of more than 10 ng/mL and those with prostate cancer were excluded.
The Medical Therapy of Prostatic Symptoms (MTOPS) trial demonstrated that combination therapy with doxazosin and finasteride was well tolerated, and was superior to placebo and monotherapy with either agent. The primary endpoints of the study were reduction in AUA-SI score, AUR, recurrent infections, renal insufficiency, incontinence, changes in flow, and PSA level and a lower rate of invasive treatments. MTOPS was a multicenter, 4- to 6-year, double-blind, randomized, placebo-controlled trial of 3,047 men with symptomatic BPH.[17]
In the Alfuzosin Long-Term Efficacy and Safety Study (ALTESS), alfuzosin (10 mg/d) decreased the risk of LUTS deterioration and significantly improved QOL and peak urinary flow rate. ALTESS was a 2-year, double-blind, placebo-controlled study of 1,522 men. Notably, these men had greater risk factors for BPH progression (ie, older age, higher IPSS scores, larger prostate size, lower Qmax, and higher PVR) than those in the MTOPS trial. Alfuzosin did not reduce the risk of AUR but tended to reduce the risk of surgery.[18]
In the international real-life practice study of alfuzosin once daily (ALF-ONE), 3 years of alfuzosin (10 mg/d) decreased IPSS by one third, with significant improvements in nocturia and bother score. ALF-ONE was conducted in 689 European men with a mean age of 67.6 years. Clinical progression of worsening of IPSS (≥4 points) was seen in 12.4%, AUR in 2.6%, and requirement of BPH-related surgery in 5.7%. Alfuzosin was well tolerated, with dizziness the most common adverse effect (4.5%). Notably, symptom worsening during treatment and high PSA levels appeared to be the best predictors of clinical progression.[19]
Four-year results in the Combination of Avodart and Tamsulosin (CombAT) study revealed that for men with prostate volumes of 30-58 mL, combination therapy with dutasteride (dual 5-alpha-reductase inhibitor) and tamsulosin (alpha-1-blocker) improved symptoms, urinary flow, and QOL better than monotherapy with either drug, although not in men who had a prostate volume of 58 mL or more.[20] The adverse-effect profile of combination therapy was similar to that of monotherapy, although drug-related adverse events were more common with combination therapy.[21] CombAT is a 4-year, multicenter, randomized, double-blind, parallel group study of 4,844 men aged 50 years or older with moderate-to-severe BPH symptoms (IPSS ≥12), prostate volume of 30 mL or greater, and a PSA level of 1.5-10 ng/mL. This study contributes to the standard of care shifting towards combined drug therapy in appropriately selected patients, while better defining the role of the alpha-blockers.[15]
Phytotherapeutic Agents and Dietary Supplements
Phytotherapeutic agents and dietary supplements are considered emerging therapy by the AUA Guidelines panel and are not recommended for the treatment of BPH because of the lack of evidence at this time.Pharmaceuticals derived from plant extracts are widely used throughout the world for the treatment of various medical ailments. In 1998, Americans spent a total of $3.65 billion on all herbal remedies. In France and Germany, plant extracts have a market share of up to 50% of all drugs prescribed for symptomatic BPH. In the United States, these agents are also popular and readily available.
The attraction to phytotherapeutic agents appears to be related to the perception of therapeutic healing powers of natural herbs, the ready availability, and the lack of adverse effects.
Most of the phytotherapeutic agents used in the treatment of LUTS secondary to BPH are extracted from the roots, seeds, bark, or fruits of plants listed below. Some suggested active components include phytosterols, fatty acids, lectins, flavonoids, plant oils, and polysaccharides. Some preparations derive from a single plant; others contain extracts from 2 or more sources.
Each agent has one or more proposed modes of action. The following modes of action are suggested:
- Antiandrogenic effect
- Antiestrogenic effect
- Inhibition of 5-alpha-reductase
- Blockage of alpha receptors
- Antiedematous effect
- Anti-inflammatory effect
- Inhibition of prostatic cell proliferation
- Interference with prostaglandin metabolism
- Protection and strengthening of detrusor
- Saw palmetto, (American dwarf palm; Serenoa repens, Sabal serrulata) fruit
- South African star grass (Hypoxis rooperi) roots
- African plum tree (Pygeum africanum) bark
- Stinging nettle (Urtica dioica) roots
- Rye (Secale cereale) pollen
- Pumpkin (Cucurbita pepo) seeds
Saw palmetto (American dwarf palm)
Extracts of saw palmetto berries are the most popular botanical products for BPH. The active components are believed to be a mixture of fatty acids, phytosterols, and alcohols. The proposed mechanisms of action are antiandrogenic effects, 5-alpha-reductase inhibition, and anti-inflammatory effects.The recommended dosage is 160 mg orally twice daily. Studies show significant subjective improvement in symptoms without objective improvements in urodynamic parameters. Minimal adverse effects include occasional GI discomfort.
The 2010 AUA guidelines, based on more recent studies, do not detect a clinically meaningful effect of saw palmetto on LUTS. Further clinical trials are underway.[2] In fact, in a double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites, saw palmetto extract was studied at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. Saw palmetto extract was no more effective than placebo on the American Urological Association Symptom Index. No clearly attributable adverse effects were identified. Similar to the Saw Palmetto Treatment for Enlarged Prostates (STEP) study, saw palmetto was not found to be beneficial for the treatment of LUTS in men.[22]
African plum tree (P africanum)
Suggested mechanisms of action include inhibition of fibroblast proliferation and anti-inflammatory and antiestrogenic effects. This extract is not well studied.Rye (S cereale)
This extract is made from pollen taken from rye plants growing in southern Sweden. Suggested mechanisms of action involve alpha-blockade, prostatic zinc level increase, and 5-alpha-reductase activity inhibition. Significant symptomatic improvement versus placebo has been reported.Treatment of Concomitant Erectile Dysfunction
It is recommended to first establish the alpha-1 blocker dose before treating the erectile dysfunction. The medication used to treat erectile dysfunction should be titrated to the lowest effective dose. Furthermore, sildenafil doses of greater than 25 mg should not be taken within 4 hours of any alpha-blocker.[23, 24, 25]In addition to treating erectile dysfunction, sildenafil may improve mild-to-moderate LUTS. Nitric oxide may mediate relaxation of the prostatic urethra and/or bladder neck. The utility of phosphodiesterase inhibitors in the treatment of LUTS has yet to be defined.[26]
Recent trials have addressed the use of long-acting phosphodiesterase type 5 inhibitors (tadalafil) and have found them to be significantly better than placebo in improving the symptoms of BPH/LUTS.
Transurethral Resection of the Prostate
TURP is considered the criterion standard for relieving BOO secondary to BPH. The indications to proceed with a surgical intervention include the following:- AUR
- Failed voiding trials
- Recurrent gross hematuria
- Urinary tract infection
- Renal insufficiency secondary to obstruction
TURP is performed with regional or general anesthesia and involves the placement of a working sheath in the urethra through which a hand-held device with an attached wire loop is placed. High-energy electrical cutting current is run through the loop so that the loop can be used to shave away prostatic tissue. The entire device is usually attached to a video camera to provide vision for the surgeon.
Although TURP is often successful, it has significant drawbacks. When prostatic tissue is cut away, significant bleeding may occur, possibly resulting in termination of the procedure, blood transfusion, and a prolonged hospital stay.
Irrigating fluid may also be absorbed in significant quantities through veins that are cut open, with possible serious sequelae termed transurethral resection syndrome (TUR syndrome). However, this is very rare and does not occur with saline irrigation used in bipolar devices. A urinary catheter must be left in place until the bleeding has mostly cleared.
The large working sheath combined with the use of electrical energy may also result in stricturing of the urethra.
The cutting of the prostate may also result in a partial resection of the urinary sphincteric mechanism, causing the muscle along the bladder outlet to become weak or incompetent. As a result, when the patient ejaculates, this sphincteric mechanism cannot keep the bladder adequately closed. The ejaculate consequently goes backwards into the bladder (ie, retrograde ejaculation), rather than out the penis. Additionally, if the urinary sphincter is damaged, urinary incontinence may result.
The nerves associated with erection run along the outer rim of the prostate, and the high-energy current and/or heat generated by such may damage these nerves, resulting in impotence.
TURP usually requires hospitalization.
Open Prostatectomy
This procedure is now reserved for patients with very large prostates (>75 g), patients with concomitant bladder stones or bladder diverticula, and patients who cannot be positioned for transurethral surgery.Open prostatectomy requires hospitalization and involves the use of general/regional anesthesia and a lower abdominal incision. The inner core of the prostate (adenoma), which represents the transition zone, is shelled out, thus leaving the peripheral zone behind. This procedure may involve significant blood loss, resulting in transfusion. Open prostatectomy usually has an excellent outcome in terms of improvement of urinary flow and urinary symptoms.
More recently, laparoscopic simple prostatectomy has been performed at a number of institutions and appears to be feasible. However, prostatectomy performed in this fashion still appears to be associated with risk for significant blood loss. Experience to date with this procedure is limited.[27]
Minimally Invasive Treatment
There is considerable interest in the development of other therapies to decrease the amount of obstructing prostate tissue while avoiding the above-mentioned adverse effects associated with TURP. These therapies are collectively called minimally invasive therapies.
Most minimally invasive therapies rely on heat to destroy prostatic tissue. This heat is delivered in a limited and controlled fashion, in the hope of avoiding the complications associated with TURP. They also allow for the use of milder forms of anesthesia, which translates into less anesthetic risk for the patient.
Heat may be delivered in the form of laser energy, microwaves, radiofrequency energy, high-intensity ultrasound waves, and high-voltage electrical energy. As in TURP, delivery devices are usually passed through a working sheath placed in the urethra, although they are usually of a smaller size than that needed for TURP. Devices may also simply be attached or incorporated into a urinary catheter or passed through the rectum, from which the prostate may also be accessed.
Keep in mind that many of these minimally invasive therapies are undergoing constant improvements and refinements, resulting in increased efficacy and safety. Ask urologists about the specifics of the minimally invasive therapies that they use and what results they have experienced.
Lasers have also been used to directly evaporate, or to melt away, prostate tissue, which is more effective than laser coagulation. Photoselective vaporization of the prostate produces a beam that does not directly come into contact with the prostate; rather, it delivers heat energy into the prostate, resulting in destruction/ablation of the prostate tissue.
Potassium-titanyl-phosphate (KTP) and holmium lasers are used to cut and/or enucleate the prostate, similar to the TURP technique. These are widely used laser techniques.
Transurethral vaporization/ablation with the KTP or holmium laser can be performed with general or spinal anesthesia and can be performed in an outpatient setting. Catheter time usually lasts less than 24 hours. Studies suggest that photoselective vaporization of the prostate can significantly improve and sustain symptomatic and urodynamic outcomes.
This procedure has been quite useful in patients who require anticoagulation for various medical conditions, since anticoagulation does not need to be interrupted for this procedure, thus further decreasing patient risk.[28, 29]
Lasers may be used in a knifelike fashion to directly cut away prostate tissue (ie, holmium laser enucleation of the prostate), similar to a TURP procedure. The holmium laser allows for simultaneous cutting and coagulation, making it quite useful for prostate resection. Laser enucleation of the prostate has proved to be safe and effective for treatment of symptomatic BPH, regardless of prostate size, with low morbidity and short hospital stay.
TUR syndrome is not seen with this technique, because iso-osmotic saline is used for irrigation. Additionally, removed prostatic tissue is available for histologic evaluation, whereas vaporization/ablation technique does not provide tissue for evaluation. Holmium laser enucleation of the prostate may prove to be the new criterion standard for surgical management of BPH.[29, 30]
Laser treatment usually results in decreased bleeding, fluid absorption, and length of hospital stay, as well as decreased incidence of impotence and retrograde ejaculation when compared with standard TURP. However, healing from laser treatment does not occur until after a period when dead cells slough; thus, patients may experience urinary urgency or irritation, resulting in frequent or uncomfortable urination for a few weeks.
The results of laser therapy vary from one another because not all wavelengths yield the same tissue effects. For example, interstitial lasers (eg, indigo lasers) are designed to heat tissue within the confines of the prostate gland and spread radiant energy at relatively low energy levels. They do not directly involve the urethral portion; thus, irritative symptoms following the procedure are potentially reduced.
Contact lasers such as KTP or holmium, on the other hand, are designed to cut and vaporize at extremely high temperatures They usually bring about more relief of urinary symptoms than treatment with medicines, but not always as much as is provided with TURP. However, KTP laser vaporization and holmium laser enucleation yield results that rival those of TURP.
TUMT can be performed in the outpatient setting with local anesthesia. Microwave treatment appears to be associated with significant prostatic swelling; a considerable number of patients require a urinary catheter until the swelling subsides. In terms of efficacy, TUMT places between medical therapy and TURP. The 2010 AUA guidelines state TUMT is an effective option for partially relieving symptoms that may be considered in patients with moderate or severe LUTS secondary to BPH.[31]
TUNA can be performed under local anesthesia, allowing the patient to go home the same day. Similar to microwave treatment, radiofrequency treatment is quite popular, and a number of urologists have experience with its use. Radiofrequency treatment appears to reliably result in significant relief of symptoms and better urine flow, although not quite to the extent achieved with TURP. The 2010 AUA guideline update considers TURP an appropriate and effective treatment option for moderate or severe LUTS.[2]
High-intensity ultrasound energy also produces moderate results in terms of improvement of the urinary flow rate and urinary symptoms, although its use is now relatively limited compared with the more popular TUNA and TUMT.
High-intensity ultrasound is considered investigational at this time and should not be offered outside of clinical trials.
Prostatic stents are flexible devices that can expand when put in place to improve the flow of urine past the prostate. Their use has been associated with encrustation, pain, incontinence, and overgrowth of tissue through the stent, possibly making their removal quite difficult. To date, their full role and long-term effects are not fully known.
Most minimally invasive therapies rely on heat to destroy prostatic tissue. This heat is delivered in a limited and controlled fashion, in the hope of avoiding the complications associated with TURP. They also allow for the use of milder forms of anesthesia, which translates into less anesthetic risk for the patient.
Heat may be delivered in the form of laser energy, microwaves, radiofrequency energy, high-intensity ultrasound waves, and high-voltage electrical energy. As in TURP, delivery devices are usually passed through a working sheath placed in the urethra, although they are usually of a smaller size than that needed for TURP. Devices may also simply be attached or incorporated into a urinary catheter or passed through the rectum, from which the prostate may also be accessed.
Keep in mind that many of these minimally invasive therapies are undergoing constant improvements and refinements, resulting in increased efficacy and safety. Ask urologists about the specifics of the minimally invasive therapies that they use and what results they have experienced.
Transurethral Incision of the Prostate
Transurethral incision of the prostate (TUIP) has been in use for many years and, for a long time, was the only alternative to TURP. It may be performed with local anesthesia and sedation. TUIP is suitable for patients with small prostates and for patients unlikely to tolerate TURP well because of other medical conditions. TUIP is associated with less bleeding and fluid absorption than TURP. It is also associated with a lower incidence of retrograde ejaculation and impotence than TURP.Lasers
Lasers deliver heat to the prostate in various ways. Lasers heat prostate tissue, causing tissue death by coagulative necrosis, with subsequent tissue contraction; however, laser coagulation of the prostate in this specific sense has met with limited results.Lasers have also been used to directly evaporate, or to melt away, prostate tissue, which is more effective than laser coagulation. Photoselective vaporization of the prostate produces a beam that does not directly come into contact with the prostate; rather, it delivers heat energy into the prostate, resulting in destruction/ablation of the prostate tissue.
Potassium-titanyl-phosphate (KTP) and holmium lasers are used to cut and/or enucleate the prostate, similar to the TURP technique. These are widely used laser techniques.
Transurethral vaporization/ablation with the KTP or holmium laser can be performed with general or spinal anesthesia and can be performed in an outpatient setting. Catheter time usually lasts less than 24 hours. Studies suggest that photoselective vaporization of the prostate can significantly improve and sustain symptomatic and urodynamic outcomes.
This procedure has been quite useful in patients who require anticoagulation for various medical conditions, since anticoagulation does not need to be interrupted for this procedure, thus further decreasing patient risk.[28, 29]
Lasers may be used in a knifelike fashion to directly cut away prostate tissue (ie, holmium laser enucleation of the prostate), similar to a TURP procedure. The holmium laser allows for simultaneous cutting and coagulation, making it quite useful for prostate resection. Laser enucleation of the prostate has proved to be safe and effective for treatment of symptomatic BPH, regardless of prostate size, with low morbidity and short hospital stay.
TUR syndrome is not seen with this technique, because iso-osmotic saline is used for irrigation. Additionally, removed prostatic tissue is available for histologic evaluation, whereas vaporization/ablation technique does not provide tissue for evaluation. Holmium laser enucleation of the prostate may prove to be the new criterion standard for surgical management of BPH.[29, 30]
Laser treatment usually results in decreased bleeding, fluid absorption, and length of hospital stay, as well as decreased incidence of impotence and retrograde ejaculation when compared with standard TURP. However, healing from laser treatment does not occur until after a period when dead cells slough; thus, patients may experience urinary urgency or irritation, resulting in frequent or uncomfortable urination for a few weeks.
The results of laser therapy vary from one another because not all wavelengths yield the same tissue effects. For example, interstitial lasers (eg, indigo lasers) are designed to heat tissue within the confines of the prostate gland and spread radiant energy at relatively low energy levels. They do not directly involve the urethral portion; thus, irritative symptoms following the procedure are potentially reduced.
Contact lasers such as KTP or holmium, on the other hand, are designed to cut and vaporize at extremely high temperatures They usually bring about more relief of urinary symptoms than treatment with medicines, but not always as much as is provided with TURP. However, KTP laser vaporization and holmium laser enucleation yield results that rival those of TURP.
Transurethral Microwave Therapy
The use of microwave energy, termed transurethral microwave therapy (TUMT), delivers heat to the prostate via a urethral catheter or a transrectal route. The surface closest to the probe (the rectal or urethral surface) is cooled to prevent injury. The heat causes cell death, with subsequent tissue contraction, thereby decreasing prostatic volume.TUMT can be performed in the outpatient setting with local anesthesia. Microwave treatment appears to be associated with significant prostatic swelling; a considerable number of patients require a urinary catheter until the swelling subsides. In terms of efficacy, TUMT places between medical therapy and TURP. The 2010 AUA guidelines state TUMT is an effective option for partially relieving symptoms that may be considered in patients with moderate or severe LUTS secondary to BPH.[31]
Transurethral Needle Ablation of the Prostate
Transurethral needle ablation of the prostate (TUNA) involves using high-frequency radio waves to produce heat, resulting in a similar process of thermal injury to the prostate as previously described. A specially designed transurethral device with needles is used to deliver the energy.TUNA can be performed under local anesthesia, allowing the patient to go home the same day. Similar to microwave treatment, radiofrequency treatment is quite popular, and a number of urologists have experience with its use. Radiofrequency treatment appears to reliably result in significant relief of symptoms and better urine flow, although not quite to the extent achieved with TURP. The 2010 AUA guideline update considers TURP an appropriate and effective treatment option for moderate or severe LUTS.[2]
High-Intensity Ultrasound Energy Therapy
High-intensity ultrasound energy therapy delivers heat to prostate tissue, with the subsequent process of thermal injury. High-intensity ultrasound waves may be delivered rectally or extracorporeally and can be used with the patient on intravenous sedation. Urinary retention appears to be common with its use.High-intensity ultrasound energy also produces moderate results in terms of improvement of the urinary flow rate and urinary symptoms, although its use is now relatively limited compared with the more popular TUNA and TUMT.
High-intensity ultrasound is considered investigational at this time and should not be offered outside of clinical trials.
Mechanical Approaches
Mechanical approaches are used less commonly and are usually reserved for patients who cannot have a formal surgical procedure. Mechanical approaches do not involve the use of energy to treat the prostate.Prostatic stents are flexible devices that can expand when put in place to improve the flow of urine past the prostate. Their use has been associated with encrustation, pain, incontinence, and overgrowth of tissue through the stent, possibly making their removal quite difficult. To date, their full role and long-term effects are not fully known.
Diet
Data from the Prostate Cancer Prevention Trial revealed that a diet low in fat and red meat and high in protein and vegetables may reduce the risk of symptomatic BPH. Additionally, regular alcohol consumption was associated with a reduced risk of symptomatic BPH, but this is to be interpreted cautiously given the untoward effects of excessive alcohol consumption.[32]Long-term Monitoring
Patients with BPH who have symptoms significant enough to be placed on medication should be evaluated during office visits to discuss the efficacy of the medication and potential dose adjustment. These visits should take place at least biannually. Patients should undergo DRE and PSA screening at least annually.
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