Benign prostatic hyperplasia is characterized by smooth muscle and epithelial proliferation primarily within the prostatic transition zone that can cause a variety of problems for a patient, the most frequent being bothersome lower urinary tract symptoms. In most cases, medical therapy has become the first-line treatment modality of choice, with a variety of pharmacologic mechanisms proving to be beneficial. Several large trials have shown the efficacy of alpha-receptor blocking and 5-alpha reductase inhibiting medications when used alone and in combination. Newer data has shown the benefit of anti-muscarinic medications in specific populations who suffer from bladder outlet obstruction causing storage urinary symptoms. Phytotherapeutic supplements are numerous and used frequently; however, data supporting safety and efficacy is limited, making treatment recommendations difficult. The available clinical trial data for all of these types of therapy is discussed in this article.
As noted in other articles in this issue, benign prostatic hyperplasia (BPH) is a histologic diagnosis that refers to the proliferation of smooth muscle and epithelial cells within the prostatic transition zone. The enlarged gland is thought to lead to disease manifestations via two routes: (1) static component: direct bladder outlet obstruction (BOO) from enlarged tissue, and (2) dynamic component: from increased smooth muscle tone and resistance within the enlarged gland. This most common manifestation of BPH is the collection of symptoms described as lower urinary tract symptoms (LUTS). LUTS are any combination of urinary symptoms, including voiding symptoms (hesitancy, weak stream, intermittency, terminal dribbling, and feeling of incomplete emptying) and storage symptoms (frequency, urgency, and nocturia). Voiding symptoms are often attributed to, but not pathognomonic for, the physical presence of BOO. Longstanding BOO and bladder overdistension may cause fibrotic changes of the bladder wall leading to changes in detrusor function (ie, detrusor instability). Detrusor instability is thought to be a contributor to the storage symptoms seen in LUTS. Less frequently, BPH has been associated with other comorbidities including acute urinary retention (AUR), renal insufficiency, development of bladder calculi, urinary incontinence, and recurrent urinary tract infection. Therapy for BPH typically targets one or both of the disease components (static or dynamic) to provide relief.
For years, the primary treatment options for BPH were surgical; however the number of prostatectomies performed for BPH-related disease has decreased from 250,000 in the mid 1980s to 88,000 in 1997. This decrease in rate of prostatectomy in the face of increasing BPH diagnoses is likely attributable to a variety of factors. One major factor is a paradigm shift to a treatment strategy focused on medical treatment of BPH in favor of surgery. The development of safe, effective medical therapies for BPH is largely responsible for this change in treatment approach.
Traditionally, the primary goal of treatment has been to alleviate bothersome LUTS that result from prostatic enlargement. More recently, treatment has additionally been directed toward alteration of disease progression and prevention of the comorbidities that can be associated with BPH. A variety of medication classes are used in BPH therapy including alpha-adrenergic antagonists, 5-alpha reductase inhibitors (5-ARI), antimuscarinics, phytotherapeutics, and the more recently explored phosphodiesterase inhibitors, intraprostatic neurotoxins, and luteinizing hormone releasing hormone (LHRH) analogs. Choosing the correct medical treatment for BPH is complex and ever changing. This article focuses on the most established medical therapies for the treatment of symptomatic BPH, and the article that follows discusses newer medical interventions.
Alpha-adrenergic antagonists
As mentioned previously, symptomatic BPH has been attributed, with various levels of evidence, to arise from two major components: static and dynamic, with an increase in prostatic smooth muscle tone believed to be largely responsible for the latter. Noradrenergic sympathetic nerves have been demonstrated to effect the contraction of prostatic smooth muscle. The prostate gland contains high levels of both α 1 – and α 2 -adrenergic receptors (ARs). Ninety-eight percent of α 1 -adrenoreceptors are associated with the stromal elements of the prostate and are thus thought to have the greatest influence on prostatic smooth muscle tone. Activation of these receptors and the subsequent increase in prostatic smooth muscle tone with urethral constriction and impaired flow of urine is thought to be a major contributor to the pathophysiology of symptomatic BPH. In addition, there is evidence that ARs further mediate the symptoms of BPH via their activation within the central nervous system (CNS) and bladder.
Alpha-ARs are not unique to the prostate. The two basic subtypes of α-receptors (α 1 and α 2 ) are distributed ubiquitously throughout the human body. In general, α 2 -receptors are typically located presynaptically and down-regulate norepinephrine release via a negative feedback mechanism. If stimulated, one expects resultant smooth muscle relaxation. α 1 -Receptors are the postsynaptic receptors that affect a response to neurotransmitter release. Several subtypes of the α 1 -adrenoreceptors have been identified and classified into three groups: α 1A , α 1B , and α 1D .
Both α 1A and α 1B -adrenoreceptors have been identified within the prostate. The α 1A receptors are the predominant adrenoreceptors expressed by stromal smooth muscle cells. In contrast, the α 1B receptors are predominantly located in the smooth muscle of arteries and veins, including the microvasculature contained within the prostate gland. Within the genitourinary system, α 1D – adrenoreceptors are mainly located in the bladder body and dome. α 1D -receptors are also located in the spinal cord where they are presumed to play a role in the sympathetic modulation of parasympathetic activity. The α 1D -receptor has been proposed to mediate the irritative components of LUTS.
The importance of the α 1 -ARs in the normal and functionally disturbed detrusor has been discussed for decades. There seems to be a general agreement that in the normal human detrusor the number of α 1 -ARs is low, and that the contractile function is almost negligible. However, the questions raised have been: do the numbers or types of α 1 -ARs and/or their function change in outflow obstruction? In the human detrusor, Malloy and colleagues found mRNA expression of both α 1D – and α 1A -receptor subtypes but no expression of α 1B . The relation between the former subtypes was α 1D : 66% and α 1A : 34%. In rats, Hampel and colleagues found that 70% of α 1 -AR mRNA was the α 1A subtype, 5% were α 1B and 25% were α 1D . Although bladder α 1 -AR density did not increase overall with obstruction, striking changes in α 1 -AR subtype expression occurred: α 1 -AR expression changed to 23% α 1A , 2% α 1B , and 75% α 1D . No functional correlates were reported. In another study from the same group, however, Gu and colleagues found evidence supporting the hypothesis that the α 1D -ARs are mechanistically involved in the development of irritative symptoms in rats and that they may be plausible targets for therapeutic intervention. In the human detrusor, Nomiya and Yamaguchi demonstrated that there was no up-regulation of any of the ARs (α- or β-AR mRNA) with obstruction. In addition, in functional experiments they confirmed previous functional results, showing that the human detrusor has a low sensitivity to α-AR stimulation—phenylephrine at high drug concentrations produced a weak contraction with no difference between normal and obstructed bladders. Thus, in the obstructed human bladder, there seems to be no evidence for α-AR up-regulation or change in subtype. This would mean that it is unlikely that the α 1D -ARs in the detrusor muscle are responsible for detrusor overactivity or the overactive bladder syndrome. This does not exclude that the α-ARs on eg, bladder vascular smooth muscle may have important roles in the changes in bladder function found after outflow obstruction.
Knowledge of α 1 -receptor subtype location and action has been instrumental in targeting BPH therapy to the correct location. Given their location, α 1A -adrenoreceptors are ideal targets for therapy. Blockade of the α 1A -adrenoreceptors has been shown to reduce prostatic tone and improve the dynamic aspects of voiding. Blockade of α 1B -receptors leads to venous and arterial dilation as smooth muscle cells in the vessel walls relax. In some patients this can cause dizziness and hypotension because of decreased total peripheral resistance, potentially serious side effects. Stimulation of α 1D -receptors can lead to detrusor overactivity, and blockade of these receptors has been shown in animal models to reduce irritative voiding symptoms. Taken together, it appears that combined antagonism of α 1A – and α 1D -receptors is, in theory, a great option for the management of BPH as it combines a reduction of prostatic smooth muscle tone with decreased detrusor instability and avoids the possible cardiovascular side effects of α 1B -receptor blockade.
As the knowledge of receptor subtypes has advanced, medications have been engineered to attempt to provide the optimal benefit of specific alpha-blockade while reducing side effects. This has led to the development of three generations of alpha-blocking medications with increasing specificity for the most desirable receptors. Following is a listing of many of the most common alpha-blocking medications with their receptor specificity profiles ( Table 1 ).
| Rank Order of Receptor | |
|---|---|
| Selectivity | |
| Prazosin | α 1A = α 1B = α 1D |
| Doxazosin | α 1A = α 1B = α 1D |
| Terazosin | α 1B = α 1D > α 1A |
| Alfuzosin | α 1A = α 1B = α 1D |
| Tamsulosin | α 1A = α 1D > α 1B |
| Silodosin | α 1A > α 1D >> α 1B |
The first generation of specific alpha-blocking agents explored and found to be useful for relief of BPH symptoms was phenoxybenzamine. Phenoxybenzamine is a nonselective α 1 /α 2 -receptor blocker that was one of the earliest alpha-blocking medications found to be effective in the therapy of BPH. The utility of this medication was limited by the frequently encountered side effects of syncope, orthostatic hypotension, reflex tachycardia, cardiac arrhythmias, and retrograde ejaculation. Most of these side effects were attributed to α 2 -receptor blockade.
In an effort to minimize side effects, second-generation alpha-blocking agents (eg, prazosin, terazosin, doxazosin, alfuzosin) were developed that were specific to α 1 -receptors and had reduced activity at α 2 -receptors. Therefore, they improve LUTS with fewer vasodilatory-related effects.
Third-generation α 1 -adrenergic antagonists (eg, tamsulosin, silodosin) are thought to be more selective antagonists for prostatic α 1A -receptors. These drugs selectively target the smooth muscle cells contained within the prostate gland and exert lesser effects on the other α-adrenergic receptor subtypes that regulate blood pressure. Therefore, these agents theoretically act in the location that will have the greatest benefit for symptoms with the fewest side effects. Second- and third-generation alpha-blocking agents remain a mainstay of BPH therapy and several will be discussed individually in the following sections.
Second Generation: Terazosin, Doxazosin, and Alfuzosin
Terazosin is an α 1 -selective antagonist with a relatively long half-life that allows for once-daily dosing. The Hytrin Community Assessment Trial demonstrates the effectiveness of this medication. In this study, 2084 men 55 years of age or older with moderate to severe urinary symptoms were randomized to receive treatment with terazosin or placebo. Terazosin was significantly superior to placebo in all measurements of efficacy; in the terazosin group, the American Urological Association International Prostate Symptom Score (AUA-IPSS) improved by 37.8%, compared with 18.4% in the placebo. The mean change from baseline in peak urinary flow rate (Qmax) was 2.2 mL/s for terazosin compared with 0.8 mL/s for placebo. Treatment failure occurred in approximately 11% of the terazosin study group, compared with approximately 25% in the placebo group. Withdrawal from the study owing to adverse effects of treatment occurred in 20% of the terazosin group and 15% of placebo patients. Terazosin is thus an effective medical treatment for reducing LUTS and the impairment of quality of life because of urinary symptoms created by BPH.
Doxazosin, a long-acting, α 1 -selective antagonist also allows for once-daily dosing. Clinical trials have demonstrated that doxazosin increases Qmax by 23% to 28% and decreases symptom scores by 16.4% versus 9.8% in placebo groups in men with symptomatic BPH. It has been shown that the response to doxazosin is dose dependent. The side-effect profile has also been shown to be dose dependent. To minimize the frequency of side effects (ie, postural hypotension and syncope), doxazosin is typically initiated at a dose of 1 mg administered once daily. Depending on response to therapy and tolerability, the dosage may be increased to 8 mg/d. Doxazosin is an effective therapy for symptomatic BPH, which like terazosin, has been shown to relieve symptoms and improve urinary flow rates.
Alfuzosin, another second-generation α 1 -adrenoreceptor antagonist, is indicated for the management of moderate to severe BPH symptoms. Alfuzosin has been shown to improve bothersome urinary symptoms and increase urine flow rates with efficacy similar to other second-generation α 1 -adrenoreceptor antagonists. Additionally, in alfuzosin trials the incidence of cardiovascular side effects are lower when compared with separate trials conducted with terazosin and doxazosin ( Table 2 ). Although a comparison across different trials does not provide the most solid evidence, this speaks to a safety profile for alfuzosin with lesser cardiovascular effects than its other second-generation counterparts. The mechanistic origin of the lesser cardiovascular effects is not entirely known, but decreased blood brain barrier penetration, preferential distribution to the prostate, and pharmacokinetic differences have been theorized to contribute. This medication comes in three formulations: immediate release (requires 2–3 daily doses), extended release (XL), and sustained-release with the latter two only requiring 1 daily dose.
| Effect | Phenoxybenzamine (%) | Prazosin (%) | Terazosin (%) | Doxazosin (%) | Tamsulosin (%) | Alfuzosin (%) | Silodosin (%) |
|---|---|---|---|---|---|---|---|
| Hypotension | 15–20 | 10–15 | 2–8 | 1–2 | <1 | <1 | <1 |
| Dizziness | 10–14 | 15–17 | 7–14 | 10–15 | 15 | 6–9 | 5 |
| Headache | 4–15 | 13–15 | 4–10 | 9–10 | 19 | 8–14 | NR |
| Sexual dysfunction | 5–8 | NR | 2–7 | NR | 8 | 1–2 | 22 |
| Fatigue | 10–15 | 10 | 4–8 | 1–2 | 8 | 1–7 | NR |
| Syncope | NR | NR | <1 | <1 | <1 | <1 | NR |
| Nasal congestion | 8 | NR | 2 | NR | 13 | 5–6 | NR |
Third Generation: Tamsulosin, Silodosin
Tamsulosin is a third-generation alpha-blocker with greater specificity for the α 1A -adrenoreceptor in relation to the α 1B -adrenoreceptor. Clinical trials suggest that tamsulosin provides relatively rapid symptom improvement and improvement in peak urinary flow rate. Early clinical trials suggested that tamsulosin increased Qmax by approximately 1.5 mL/s and decreased AUA-IPSS scores by more than 35%. Long-term studies (up to 60 weeks) examining the effects of tamsulosin demonstrate its beneficial effects are sustained over time, as measured by maximal urinary flow rates and symptoms score. The most common side effects reported with tamsulosin use are dizziness (∼5%) and retrograde ejaculation (∼8%). Clinical studies have also demonstrated that tamsulosin can be coadministered with antihypertensive medications such as nifedipine, enalapril, and atenolol without any increased risk of hypotensive or syncopal episodes. Tamsulosin is thus, a safe and efficacious drug for the treatment of BPH with fewer documented cardiovascular side effects than the other available alpha-blocking medications.
Silodosin, one of the most recently approved alpha-blocking medications for BPH, is a third-generation medication with reported α 1A versus α 1B affinity 38 times greater than tamsulosin. There is limited published evidence to date as to the effectiveness of silodosin. This information hails from the phase 3 clinical trial performed in Japan using a lower dose of tamsulosin (0.2 mg) than available elsewhere. This 12-week trial enrolled 457 men who met inclusion criteria and enrolled them in three groups: silodosin 4 mg twice daily, tamsulosin 0.2 mg once daily (standard Japanese dose), and placebo. Mean AUA-IPSS improvement was significantly better when compared with placebo (−8.3 vs −5.3) but there was not a significant improvement in AUA-IPSS when compared with tamsulosin. Across the three groups, there were 1.70 mL/s, 2.60 mL/s, and 0.26 mL/s improvements in Qmax in the silodosin, tamsulosin, and placebo groups, respectively ( P = .063 vs tamsulosin; P = .005 vs placebo). There were −1.7, −1.4, and −1.1 improvements in quality of life (QOL) questions in the silodosin, tamsulosin, and placebo groups, respectively ( P = .052 vs tamsulosin; P = .002 vs placebo). Adverse event rates were relatively similar with the exception that the rate of ejaculatory dysfunction in the silodosin group was 22.3% versus 1.6% in the tamsulosin group and 0% in the placebo group (no significance data provided). There were no clinically significant differences of blood pressure or heart rate and dizziness rates were 5.1% versus 7.3% (no significance data provided) between the silodosin and tamsulosin groups, respectively. Thus, this study provides evidence that silodosin is more effective than placebo but provides no evidence that silodosin is more effective than other alpha blockers. Given the lack of evidence for lesser side effects than tamsulosin, it cannot be currently concluded that the silodosin’s increased α 1A versus α 1B affinity offers any additional significant clinical benefit. More data from longer-term studies would be useful in solidly establishing the true effectiveness of this medication as well as it side-effect profile.
Adverse Effects of α-Adrenergic Antagonists
Depending on dosage and selectivity, all α-adrenergic antagonists can be associated with adverse reactions (see Table 2 ). Dizziness is the most common side effect of α-adrenergic antagonists. Dizziness is thought to be caused by effects on the central nervous system or other unconventional drug mechanisms that may be unrelated to effects on the blood vessels themselves. This is supported by the finding that some dizziness can be seen with tamsulosin (a selective α 1A -adrenergic antagonist), a medication thought to have a lesser effect on blood vessels than the other medications of this class. Hypotension decreases with longer-acting drugs, and occurs least with α 1A -adrenergic selective agents. Dizziness and hypotension are more common in those older than 65 years. Ejaculatory dysfunction may occur, and although not entirely understood, is thought to possibly result from medication interactions with the vas deferens.
Hormonal therapy
The exact mechanisms and molecular pathways that lead to the histologic development of BPH are yet to be fully explained. However, current theories assert BPH is a multifactorial process involving interactions between prostatic cells, the endocrine system, neural input, heredity, and environmental influences. Although the full mechanistic pathways are not entirely known, a major contributor to the development of BPH has been shown to be the male androgen hormones testosterone and dihydrotestosterone (DHT).
Testosterone is the primary circulating androgen. Before testosterone can exert its effects on the prostatic cells, it undergoes local modification within the prostate to become DHT; 5α-reductase is responsible for this conversion. DHT then forms a complex with androgen receptors, and is transported to the nucleus. Within the nucleus, this complex acts to modify gene expression. The influence of androgens is vital to normal development and growth of the prostate gland. However, the effects of androgens have been shown to also play a role in the development of the prostatic overgrowth seen in BPH. Androgens lead to overall enlargement of the gland contributing to the static component of BPH.
In an effort to curb the production of the active compound, DHT, medications have been developed that specifically target and inhibit the enzyme 5α-reductase. Finasteride and dutasteride are examples of available 5-ARIs. These compounds virtually eliminate the production of DHT, in turn inhibiting prostate growth. The blockade of DHT production has been associated with a reduction of prostatic volume with the maximal reduction coming within 6 months of therapy initiation.
Finasteride
Finasteride is a competitive inhibitor of the type 2 isozyme of 5α-reductase. The North American Finasteride trial was the first study to report the efficacy of finasteride. This 1-year randomized, double-blind, placebo-controlled multicenter trial demonstrated that patients taking finasteride had a mean decrease in intraprostatic and circulating DHT levels of 80% that was sustained for the 12 months of treatment. There was no significant change in circulating serum testosterone levels in the treatment group, indicating there was not a positive feedback increase in testosterone levels as a result of lowered DHT. This study demonstrated Qmax increased by 1.6 mL/s, compared with 0.2 mL/s in the placebo group. The symptom score decreased an average of 2.7% in the finasteride group compared with 1.0% in the placebo group.
The Proscar Long-Term Efficacy and Safety Study (PLESS) trial is the largest clinical study to investigate finasteride therapy for BPH. This double-blind, placebo-controlled, multicenter study conducted in the United States was composed of 3040 men with moderate to severe LUTS who were randomized to a finasteride group (5 mg/d) or a placebo group for the course of a 4-year trial. At the completion of the trial, the finasteride group showed a 2.0-point greater reduction from their pre-enrollment symptom scores than did the placebo group. The finasteride group also showed a 1.7 mL/s greater improvement in Qmax and displayed a 32% reduction in prostate volume. The greatest impact from this study came from the demonstration that over the course of 4 years, compared with placebo, the finasteride group had a 57% risk reduction for the development of acute urinary retention (AUR) and a 55% risk reduction in the need for BPH-related surgery. In men with a prostate larger than 55 cm 3 there was a 70% risk reduction for the development of AUR and/or need for surgery. These new findings suggested that long-term 5-ARI therapy could impact the progression of BPH by reducing the risk of AUR and the need for surgery. Given the findings of this trial, it is recommended that patients with a prostate larger than 30 g or with moderate to severe BPH symptoms consider a 5-ARI as it may alter the condition’s natural history.
Dutasteride
Dutasteride is a dual inhibitor of both the type-1 and type-2 5α-reductase isozymes. The major source of the DHT that plays a relevant role in the prostatic enlargement seen in BPH is thought to be the type-2 5α-reductase isozyme found mostly in the prostate; however, the type-1 5α-reductase in the liver, skin, and small amount in the prostate, may also play a role in prostatic enlargement. Dutasteride was thus developed to block DHT production from both enzymatic sources.
Like finasteride, dutasteride has been shown to significantly suppress DHT levels (>90%) and has been associated with decreasing LUTS caused by BPH. It has been associated with a significant decrease in prostate volume (∼50%), increase in Qmax (∼30%), decreased risk of AUR, and decreased risk of requiring BPH-related surgery compared with placebo. This provides evidence that like finasteride, dutasteride is useful in altering the disease course of BPH.
Adverse Effects of 5-ARI Therapy
Side effects with finasteride and dutasteride are relatively infrequently encountered. The most common side effects are impotence, loss of libido, ejaculatory dysfunction, and gynecomastia ( Table 3 ), but these occur with much less frequency than with other anti-androgenics that have larger effects on circulating androgens and will be discussed later (ie, LHRH antagonists).
| Effect | Finasteride (%) | Dutasteride (%) |
|---|---|---|
| Impotence | 5.1 | 0.8–4.7 |
| Loss of libido | 2.6 | 0.3–3.0 |
| Ejaculatory disorder | 1.7 | 0.1–1.4 |
| Gynecomastia | 1.8 | 0.6–1.1 |
5-ARI Therapy and Prostate Cancer
Prostate-specific antigen (PSA) is an enzyme produced by the prostate gland detectable at low levels in the blood of all male patients. It has been shown that most men with prostate cancer have elevations of their PSA level. The prostatic enlargement seen in BPH has also been associated with a rise in PSA, although it is thought that a slower rise with a milder total elevation is more typical of BPH than the elevations seen in cancer. Because of its ability to enhance early detection of prostate cancer (albeit with some controversy over the specificity and thus utility of the test), PSA has become a commonly used screening technique for malignancy.
Treatment with finasteride decreases serum PSA levels by approximately 50% over a 4- to 6-month time period. This can lead to difficulty interpreting PSA values in a patient on a 5-ARI for BPH. Oesterling and colleagues suggested a mathematical doubling of the serum PSA level approximates the true PSA to a level accurate enough for adequate use as a cancer screening tool in 5-ARI treated patients.
There are no official recommendations to screen 5-ARI–treated patients any differently from the general population. However, given the derangements of PSA seen on 5-ARI therapy, it is wise to obtain a baseline PSA before the start of therapy. On follow-up screening, any sustained increases in PSA levels during 5-ARI treatment should be carefully evaluated and consideration given for a prostate biopsy.
The role 5-ARI therapy plays on the natural course of prostate cancer has not been fully elucidated. The large multicenter Prostate Cancer Prevention Trial showed that daily finasteride therapy was accompanied by a statistically significant 24.8% reduction in prostate cancer prevalence over a 7-year period. However, the same study also showed an increase (4.8% with high grade: placebo, 5.8% with high grade: finasteride) in the clinical grade of prostate cancer in patients who were taking finasteride. This suggests that although finasteride therapy led to a lower prevalence of cancer, the cases that were discovered in patients on finasteride were of a higher clinical grade and thus potentially more aggressive. As a result, the authors of that study concluded it is important to weigh the benefit of lower cancer prevalence and improvement of urinary symptoms with the increased risk of high-grade prostate cancer. A follow-up report from several authors of this trial suggested finasteride may actually selectively inhibit low-grade cancer cells within a tumor, making the tumor appear to be of higher grade. They suggest this may account for the greater incidence of high-grade tumors with finasteride and not effects on tumor morphology leading to induction of high-grade tumors.
A similar, yet to be published, study investigated the effect of Dutasteride on the incidence of prostate cancer in men with PSA between 2.5 and 10.0. The results of the REduction by DUtasteride of prostate Cancer Events trial were presented at the 2009 annual meeting of the American Urological Association (AUA) and are to be published later in 2009. The preliminary summary released by the AUA reported a statistically significant 23% reduction in prostate cancer incidence over 4 years. Of important note there was no significant difference in tumor grade between the Dutasteride and placebo groups.
Hormonal therapy
The exact mechanisms and molecular pathways that lead to the histologic development of BPH are yet to be fully explained. However, current theories assert BPH is a multifactorial process involving interactions between prostatic cells, the endocrine system, neural input, heredity, and environmental influences. Although the full mechanistic pathways are not entirely known, a major contributor to the development of BPH has been shown to be the male androgen hormones testosterone and dihydrotestosterone (DHT).
Testosterone is the primary circulating androgen. Before testosterone can exert its effects on the prostatic cells, it undergoes local modification within the prostate to become DHT; 5α-reductase is responsible for this conversion. DHT then forms a complex with androgen receptors, and is transported to the nucleus. Within the nucleus, this complex acts to modify gene expression. The influence of androgens is vital to normal development and growth of the prostate gland. However, the effects of androgens have been shown to also play a role in the development of the prostatic overgrowth seen in BPH. Androgens lead to overall enlargement of the gland contributing to the static component of BPH.
In an effort to curb the production of the active compound, DHT, medications have been developed that specifically target and inhibit the enzyme 5α-reductase. Finasteride and dutasteride are examples of available 5-ARIs. These compounds virtually eliminate the production of DHT, in turn inhibiting prostate growth. The blockade of DHT production has been associated with a reduction of prostatic volume with the maximal reduction coming within 6 months of therapy initiation.
Finasteride
Finasteride is a competitive inhibitor of the type 2 isozyme of 5α-reductase. The North American Finasteride trial was the first study to report the efficacy of finasteride. This 1-year randomized, double-blind, placebo-controlled multicenter trial demonstrated that patients taking finasteride had a mean decrease in intraprostatic and circulating DHT levels of 80% that was sustained for the 12 months of treatment. There was no significant change in circulating serum testosterone levels in the treatment group, indicating there was not a positive feedback increase in testosterone levels as a result of lowered DHT. This study demonstrated Qmax increased by 1.6 mL/s, compared with 0.2 mL/s in the placebo group. The symptom score decreased an average of 2.7% in the finasteride group compared with 1.0% in the placebo group.
The Proscar Long-Term Efficacy and Safety Study (PLESS) trial is the largest clinical study to investigate finasteride therapy for BPH. This double-blind, placebo-controlled, multicenter study conducted in the United States was composed of 3040 men with moderate to severe LUTS who were randomized to a finasteride group (5 mg/d) or a placebo group for the course of a 4-year trial. At the completion of the trial, the finasteride group showed a 2.0-point greater reduction from their pre-enrollment symptom scores than did the placebo group. The finasteride group also showed a 1.7 mL/s greater improvement in Qmax and displayed a 32% reduction in prostate volume. The greatest impact from this study came from the demonstration that over the course of 4 years, compared with placebo, the finasteride group had a 57% risk reduction for the development of acute urinary retention (AUR) and a 55% risk reduction in the need for BPH-related surgery. In men with a prostate larger than 55 cm 3 there was a 70% risk reduction for the development of AUR and/or need for surgery. These new findings suggested that long-term 5-ARI therapy could impact the progression of BPH by reducing the risk of AUR and the need for surgery. Given the findings of this trial, it is recommended that patients with a prostate larger than 30 g or with moderate to severe BPH symptoms consider a 5-ARI as it may alter the condition’s natural history.
Dutasteride
Dutasteride is a dual inhibitor of both the type-1 and type-2 5α-reductase isozymes. The major source of the DHT that plays a relevant role in the prostatic enlargement seen in BPH is thought to be the type-2 5α-reductase isozyme found mostly in the prostate; however, the type-1 5α-reductase in the liver, skin, and small amount in the prostate, may also play a role in prostatic enlargement. Dutasteride was thus developed to block DHT production from both enzymatic sources.
Like finasteride, dutasteride has been shown to significantly suppress DHT levels (>90%) and has been associated with decreasing LUTS caused by BPH. It has been associated with a significant decrease in prostate volume (∼50%), increase in Qmax (∼30%), decreased risk of AUR, and decreased risk of requiring BPH-related surgery compared with placebo. This provides evidence that like finasteride, dutasteride is useful in altering the disease course of BPH.
Adverse Effects of 5-ARI Therapy
Side effects with finasteride and dutasteride are relatively infrequently encountered. The most common side effects are impotence, loss of libido, ejaculatory dysfunction, and gynecomastia ( Table 3 ), but these occur with much less frequency than with other anti-androgenics that have larger effects on circulating androgens and will be discussed later (ie, LHRH antagonists).
Related posts:
Etiology, Epidemiology, and Natural History
Benign Prostatic Hyperplasia: Symptoms, Symptom Scores, and Outcome Measures
KTP/LBO Laser Vaporization of the Prostate
Minimally Invasive Therapy of Lower Urinary Tract Symptoms
Treatment of Bladder Diverticula, Impaired Detrusor Contractility, and Low Bladder Compliance
Genitourinary Pain Syndromes, Prostatitis, and Lower Urinary Tract Symptoms
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
