By inhibiting the conversion from testosterone to dihydrotestosterone 5-Alpha reductase inhibitors (5ARIs) are able to hinder prostatic growth, shrink prostate volumes, and improve BPH-related LUTS. 5ARIs are particularly beneficial for patients with larger prostates (>30–40ml). Generally the side effects of 5ARI treatment are mild, and according to the FORTA classification 5ARIs are suitable for frail elderly. 5ARI / alpha-blocker (AB) combination therapy showed the best symptomatic outcome and risk reduction for clinical progression. Combining Phosphodieseterase type 5 inhbibitors (PDE5Is) with 5ARIs counteracts the negative androgenic sexual side effects of 5ARIs, and simultaneously combines their synergistic effects on LUTS.
Key points
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In men suffering from benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS), 5-alpha reductase inhibitors (5ARIs) are a treatment option when prostate size is greater than 30 to 40 mL and medical treatment is intended for longer than 1 year.
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In the same patients, combination of 5ARIs with alpha-adrenergic-blockers (ABs) is a better option in regard to symptomatic improvement and reduction of disease progression if they are suitable for potential AB-related side effects.
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Potential sexual side effects of 5ARIs and 5ARI/AB combinations might be an individual exclusion criterion and should be openly discussed with each patient.
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5ARIs are not recommended for the prevention of BPH/LUTS or prostate cancer (PCa). Patients with BPH/LUTS undergoing 5ARI therapy should be routinely screened for PCa, at which time the serum prostate-specific antigen level should be doubled.
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Combination of phosphodiesterase type 5 inhibitors with 5ARIs might be the best medical treatment option for some patients; however, more clinical evidence is needed.
Introduction
5-Alpha-reductases (5ARs) are enzymes converting testosterone into dihydrotestosterone (DHT). DHT is the most important hormone for the development and function of male sex organs. Genetic defects of 5ARs can result in pseudohermaphroditism, meaning a female phenotype despite the presence of XY genotype. In 1940, Charles Huggins first reported the relationship between testosterone and benign prostatic hyperplasia (BPH) development. In the 1970s, the crucial role of 5AR-depending testosterone to DHT transformation in BPH development became apparent by the seminal works of Jean Wilson. Realizing the therapeutic potential of DHT regulation resulted in a quest for an 5AR-inhibitor (5ARI), which ended in 1992 with the approval of finasteride (FIN; Proscar) by the US Food and Drug Administration (FDA). In 2002, the FDA approved dutasteride (DUT; Avodart) as another 5ARI. According to current guidelines, both 5ARIs can be used in the treatment of BPH with lower urinary tract symptoms (LUTS), either alone or in combination with other drugs targeting BPH/LUTS.
Introduction
5-Alpha-reductases (5ARs) are enzymes converting testosterone into dihydrotestosterone (DHT). DHT is the most important hormone for the development and function of male sex organs. Genetic defects of 5ARs can result in pseudohermaphroditism, meaning a female phenotype despite the presence of XY genotype. In 1940, Charles Huggins first reported the relationship between testosterone and benign prostatic hyperplasia (BPH) development. In the 1970s, the crucial role of 5AR-depending testosterone to DHT transformation in BPH development became apparent by the seminal works of Jean Wilson. Realizing the therapeutic potential of DHT regulation resulted in a quest for an 5AR-inhibitor (5ARI), which ended in 1992 with the approval of finasteride (FIN; Proscar) by the US Food and Drug Administration (FDA). In 2002, the FDA approved dutasteride (DUT; Avodart) as another 5ARI. According to current guidelines, both 5ARIs can be used in the treatment of BPH with lower urinary tract symptoms (LUTS), either alone or in combination with other drugs targeting BPH/LUTS.
5-Alpha-reductase inhibitor monotherapy
Finasteride
After several animal experiments, MK-906 (which later became FIN) was successfully tested for safety, tolerability, and biochemical activity in 350 volunteers. In healthy men, MK-906 reduced serum DHT levels by −62% to −82% without affecting serum testosterone levels. Intraprostatic DHT levels were reduced by −92% in men awaiting prostate surgery.
In a phase III clinical trial, 895 men with BPH received either placebo (PBO) or FIN 1 to 5 mg for 1 year. The Boyarski score (a precursor of the American Urological Association symptom score [AUA-SS] or the international prostate symptom score [IPSS]) was significantly reduced by −2.7 with 5 mg FIN compared with no changes with PBO and 1 mg FIN. The urinary flow rate (Q max ) significantly increased from 5.6 to 6.4 mL/s with 5 mg FIN and from 5.3 to 6.1 mL/s with 1 mg FIN but remained at baseline with PBO (5.6 and 5.8 mL/s). Prostate size was reduced by −19% compared with baseline with 5 mg FIN, by −18% with 1 mg FIN, and insignificantly by −3% with PBO. In an open-label extension 186 men continued to take 5 mg FIN for 4 more years. Prostate volume reached a nadir at 24 months (−24% of initial size) and was maintained for the rest of the study. Similarly the symptom score improvement of −4.3 points and the increase of Q max by 2.3 mL/s were maintained for 4 years.
In another trial, 3040 men with BPH received either FIN 5 mg or PBO for 4 years. AUA-SS was reduced by −3.3 with FIN and by −1.3 with PBO. Prostate volume was reduced by −18% with FIN and increased by 14% with PBO. Q max improved by 1.9 mL/s with FIN and remained at 0.2 mL/s with PBO. However, the most remarkable findings were a −57% risk reduction of acute urinary retention (AUR) and a −55% risk reduction to undergo prostate surgery when taking FIN. This effect was confirmed and sustained in an open-label extension, in which 908 subjects took part for another 2 years. Subjects who switched from PBO to FIN during extension showed at study end the same AUR reduction and prostate surgery incidence as the continuous FIN arm.
Various other clinical trials compared FIN 5 mg versus PBO and reported similar outcomes, which means a reduction of prostate size by −15% to −21%, an IPSS (or similar score) reduction by −13% to −38%, and an increase of Q max by 1.6 to 2.2 mL/s. In all studies, these effects were measurable after 6 to 12 months. Meta-analysis revealed that the difference in improvement between FIN and PBO becomes significant when the prostate volume is greater than 40 mL at baseline. According to a Cochrane systematic database review, the symptomatic improvements of FIN occur distinctly later than the effects of alpha-blockers (ABs). However, when taken longer than 1 year, FIN reduces BPH progression and the risk to undergo prostate surgery, which is not an effect of ABs.
Summing up all evidence, and according to current guideline recommendations, FIN monotherapy is a treatment option in men with moderate to severe LUTS and an enlarged prostate (>40 mL). FIN should not be used in men with LUTS without prostatic enlargement. Furthermore, FIN can be used to prevent disease progression in regard to AUR and the need for surgery. Due to the low onset of action, FIN is only suitable for long-term treatment.
Dutasteride
In a study, 4325 men with clinical BPH received either DUT 0.5 mg or PBO over a 2 year period. At study end, serum DHT was reduced by −92%, prostate size by −25%, AUA SS by −4.5 points, and Q max was increased by 2.2 mL/s with DUT. Risk reduction for AUR was −57%, and −48% for prostatic surgery compared with PBO. In an open-label extension, 1570 subjects were enrolled. After 2 more years, prostate size was reduced by −26%, AUA-SS by −6.1, and Q max increased by 2.8 mL/s with DUT. The values for subjects, who switched from PBO to DUT were −20% prostate size, −5.3 AUA-SS, and +1.8 mL/s Q max . The effects of DUT were faster and more pronounced the greater the prostate volume was at baseline. In a post hoc analysis of the Reduction by DUT of Prostate Cancer Events (REDUCE) study, 1617 men with a prostate greater than 40 mL were evaluated. Clinical progression, as defined by either AUR, need for prostatic surgery, or symptom deterioration defined by an IPSS increase greater than 4, occurred in 36% of PBO and 21% of DUT subjects, translating into an absolute risk reduction by −15% and a relative risk reduction of −41%.
Whereas FIN inhibits the 5AR isoform type II, DUT inhibits 5AR isoform type I and type II; therefore it is called a dual inhibitor. Post hoc analysis suggests that the effects of DUT, in contrast to FIN, are also significant in subjects with a prostate size between 30 to 40 mL. However, different inclusion criteria in the clinical trials evaluating FIN and DUT make it difficult to directly compare these 5ARIs. The Enlarged Prostate International Comparator Study (EPICS) was designed to evaluate differences between DUT and FIN. In this trial, 1630 men with BPH received either DUT 0.5 mg or FIN 5 mg for 1 year. There were no significant differences in regard to prostate size, AUA-SS reduction, Q max improvement, or the timely onset of their effects. Hence, the pharmacological differences between those 2 compounds are not represented by any meaningful clinical difference, at least in regard to BPH/LUTS treatment. Accordingly, the guideline recommendation for DUT is the same as that for FIN, which is a long-term therapeutic option in men with moderate to severe LUTS and an increased prostate size (>40 mL).
Side Effects and Further Aspects of 5-Alpha-Reductase Inhibitors
Adverse side effects
Erectile dysfunction (ED), decreased libido, ejaculatory disorders (EjDs), and gynecomastia are the only adverse side effects that consistently occur significantly more often with 5ARIs than with PBO in various clinical trials. In a review evaluating studies ranging from 6 to 54 months, FIN increased episodes of ED by 15%, DUT by 11.0%, and PBO by 6%. EjD increased by 7% with FIN, by 3% with DUT, and by 0.1% to 1% with PBO. Decreased libido occurred 18% more often with FIN, by 6% with DUT, and by 3% to 6% with PBO. In another retrospective analysis, however, FIN was reported to have fewer sexual side effects than DUT. In 378 men treated for 5 years with 5ARIs, the incidence of ED, EjD, and decreased libido leading to discontinuation from therapy occurred in 2.1%, 1.8%, and 1.4% with FIN, and in 5.1%, 2.4%, and 2.7%, with DUT, respectively. Additionally self-reported gynecomastia was reported in 3.5% with DUT and in 1.2% with FIN. EPICS, which was the only trial directly comparing FIN versus DUT, reported no significant difference regarding any adverse side effect. ED occurred in 8% to 9% with 5ARI, decreased libido in 5% to 6%, EjD in 2%, and gynecomastia in 1%. Drug-related adverse events (AEs) leading to study withdrawal occurred in 3% of 5ARI treated subjects during 2 years. The Proscar Long-term Efficacy and Safety Study (PLESS) reported that men treated with FIN experience sexual side effects within the first year of drug treatment but not thereafter. Similarly, it was reported for DUT that the incidence of sexual AEs decreased with longer therapy duration. Even though side effects of 5ARIs are generally considered to be mild, the possibility of sexual side effects should be openly discussed with a patient before commencing therapy.
Due to their good tolerability and safety, 5ARIs are considered suitable or beneficial drugs for older patients and frail elderly people according to the Fit For Age (FORTA) classification. 5ARI were reported to not negatively affect bone mineral density, serum lipoprotein, or hemoglobin levels. Neither FIN nor DUT were reported to increase bone fracture risk. In older hypogonadal men suffering from musculoskeletal negative effects of testosterone deficiency (serum testosterone concentration <300 ng/dL), testosterone replacement therapy (125 mg/wk) could be successfully coadministered with FIN 5 mg. After 1 year of combined treatment, subjects showed increased muscle strength and bone mineral density, with simultaneously increased serum testosterone levels and still lowered serum DHT levels, compared with PBO or FIN alone. Prostate size significantly increased by 5.3 mL in the testosterone group, decreased by −5.7 mL with FIN, and stayed at baseline with testosterone/FIN and with PBO alone. FIN alone did not affect muscle strength or bone mineral density. However, the study included only 60 subjects. Another very small study reported significant prostate size reduction by DUT in men with an ongoing testosterone replacement therapy. Evidence is too scarce to give recommendations; however, testosterone replacement therapy with simultaneous 5ARI therapy might be a therapeutic option in selected patients undergoing close-meshed follow-up. The effects of testosterone/5ARI combination on prostate cancer risk are not known.
Further aspects
Additionally to its use in the treatment of BPH/LUTS, FIN is approved and used for the treatment of androgenetic alopecia. For this indication, FIN is available in a 1 mg formulation (Propecia), which is not recommended to be used for BPH/LUTS treatment.
5ARIs can affect prostatic bleeding. In small studies FIN was shown to reduce the risk of prostatic hematuria recurrence. The AUA states in the guidelines that FIN is a treatment alternative in men with refractory hematuria due to prostatic bleeding after exclusion of any other cause. This view is not shared with the European Association of Urology (EAU) guidelines. Similarly, FIN might be successfully used in the treatment of refractory hematospermia. However, available literature is too scarce to give any recommendation. Some investigators report decreased intraoperative blood loss during transurethral resection of the prostate (TURP) and consequently reduced need for blood transfusions in patients undergoing 5ARI treatment. Some investigators report that this blood-saving effect of 5ARIs could also be reached with a short-term (6–8 weeks) preoperative treatment. However, this beneficial effect of 5ARI treatment seems to be restricted to patients with rather large prostates (>50 mL). Also, 5ARI might make certain operations, such as laser enucleations, even more difficult to perform. A recent meta-analysis, including 1489 subjects, stated that there was a significant reduction of blood loss per gram of resected prostate tissue in favor of 5ARIs; however, there was no significant reduction of blood transfusions or operative time with 5ARI compared with PBO or no treatment. The AUA states that there is insufficient evidence to recommend 5ARIs preoperatively to TURP.
Data from 9253 men without BPH/LUTS from the Prostate Cancer Prevention Trial (PCPT) suggest that FIN could have a role in the prevention of incident BPH because 18.6 per 1000 person-years in the PBO but only 11.2 per 1000 person-years in the FIN group developed incident BPH, defined as first event of medical or surgical treatment, or sustained BPH symptoms in the form of an IPSS greater than 14. In other words, the number needed to treat (NNT) to prevent 1 case of clinical BPH over 7 years was 58 for men aged 55 to 59, 42 for men aged 60 to 64, and 31 for men 65 years and older. However, due to the controversies regarding 5ARIs and prostate cancer risk, the use of 5ARIs in BPH prevention should be considered very carefully. Current guidelines make no statement about the use of 5ARIs in BPH prevention.
Effects of 5-alpha-reductase inhibitors on prostate-specific antigen levels and prostate cancer risk
5ARIs are known to reduce serum prostate-specific antigen (PSA) levels and, as such, limit the value of serum PSA in PCa screening if not considered. The Finasteride PSA Study Group recommends doubling the measured serum PSA level in BPH patients taking 5ARIs so that a PCa diagnosis is not masked. The same recommendation was given by the PLESS group and other investigators. After 7 years of 5ARI treatment, serum PSA level should be corrected by the factor 2.5.
Triggered by a surprising post hoc finding of the Combination of Avodart and Tamsulosin (CombAT) trial, in which subjects receiving DUT had a lower rate of positive prostate biopsies, a passionate discussion regarding the role of 5ARI in PCa prevention started and resulted in the initiation of 2 large trials: PCPT and REDUCE. In these trials, 18,882 men older than 55 years without BPH received either FIN or PBO for 7 years. During this period, PCa was reduced by almost −25% with FIN. However, those desirable effects were counterweighed by the finding that the number of high-risk PCa was significantly higher in the FIN (37%) than in the PBO group (22%). Similarly, REDUCE reported a −22% risk reduction of PCa diagnosis with DUT. At the same time the likelihood to get diagnosed with a high-risk PCa was significantly higher with DUT than with PBO. Those controversial findings resulted in a debate about the pros and cons of 5ARI treatment in PCa prevention. To address this issue, the FDA performed an extensive work-up (including histological re-examination of specimen and various statistical calculations). Their final conclusion was that 5ARIs indeed increases the risk for high-grade PCa and excluded any bias or confounding factor. The FDA summed up that there is no acceptable risk to benefit ratio; thus 5ARI cannot be recommended routinely for PCa prevention.
The Health Professionals Follow-up Study includes a prospective cohort of 51,529 men since 1986. Out of this cohort, 2878 men could be identified who had taken a 5ARI. At the same time, 3681 men were diagnosed with PCa and 289 had died from it. In this observational study, no correlation between high-risk or lethal PCa and 5ARI intake could be established. Guidelines recommend that men taking 5ARIs for BPH/LUTS should be routinely screened for PCa using serial PSA testing.
The role of 5ARI in the treatment of low-risk cancers, as currently evaluated in some studies, is not within the scope of this article. It just should be said that 5ARI in the treatment of PCa is currently not a valid treatment option and should only be offered in the context of approved clinical trials.
5-Alpha-reductase inhibitor combination therapy
Combination with Alpha-Blockers
Alpha-adrenergic receptor antagonists (ie, ABs) are still the first-line option in men with moderate to severe BPH/LUTS suitable for drug therapy. This might be well explained by the high clinical efficacy of ABs, their low adverse side effect profile, their quick onset of action, and their low costs. Looking into real-life practice patterns, ABs are by far the most commonly prescribed drugs for BPH/LUTS. Among the different ABs available, there seem to be no meaningful clinical differences. Combining ABs with 5ARIs not only holds the prospect to be more effective in terms of clinical BPH/LUTS improvement but also combines the quick onset of action of ABs with the long-term beneficial effects of reduced BPH progression of 5ARIs.
The first clinical studies combining 5ARIs with ABs in BPH/LUTS subjects were performed in Japan during the 1990s. Since then, 6 larger randomized controlled trials assessing this combination have been performed: the Veterans Affairs Cooperative (VA-COOP) study ; the Alfuzosin, Finasteride, and combination in the treatment of BPH (ALFIN) study ; the Prospective European Doxazosin and Combination Therapy (PREDICT) study ; the Medical Therapy of Prostatic Symptoms (MTOPS) study ; CombAT ; and, just recently, the Comparative efficacy of Dutasteride plus Tamsulosin (CONDUCT) study. Additionally, countless post hoc subgroup analyses to these trials have been published.
VA-COOP, ALFIN, and PREDICT could not demonstrate any advantage of 5ARI/AB combination over AB monotherapy in regard to IPSS or AUA-SS reduction, and Q max increase; and no advantage over 5ARI monotherapy in regard to prostate size reduction. VA-COOP, ALFIN, and PREDICT had study durations of less than 1 year ( Table 1 ). MTOPS and CombAT, which lasted 4 to 6 years, showed significant advantages of 5ARI/AB combination over either monotherapy. Apart from differences in the study designs, such as different primary end points, the different outcomes between short-term and long-term trials still suggest that the beneficial effects of 5ARI/AB combination do not occur before 1 year.
| Trial | Subjects | Duration (mo) | 5-ARI | AB | IPSS or AUA-SS | Q max (mL/s) | Prostate Size (mL or %) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 5-ARI | AB | PBO | COM | 5-ARI | AB | PBO | COM | 5-ARI | AB | PBO | COM | |||||
| VA-COOP | 1229 | 12 | FIN 5 mg | Terazosin 10 mg | −3.2 | −6.1 | −2.6 | −6.2 | +1.6 | +2.7 | +1.4 | +3.2 | −6.1 | +0.5 | +0.5 | −7.0 |
| ALFIN | 1051 | 6 | FIN 5 mg | Alfuzosin 2 × 5 mg | −5.2 | −6.3 | — | −6.1 | +1.6 | +1.8 | — | +2.3 | −4.3 | −0.2 | — | −4.9 |
| PREDICT | 1095 | 12 | FIN 5 mg | Doxazosin 4–8 mg | −6.6 | −8.3 | −5.7 | −8.5 | +1.8 | +3.6 | +1.4 | +3.8 | — | — | — | — |
| MTOPS | 3047 | 54–72 | FIN 5 mg | Doxazosin 4–8 mg | −5.6 | −6.6 | −4.9 | −7.4 | +2.2 | +2.5 | +1.4 | +3.7 | −19% | +24% | +24% | −19% |
| CombAT | 3822 | 24–48 | DUT 0.5 mg | Tamsulosin 0.4 mg | −5.3 | −3.8 | — | −6.3 | +2.0 | +0.7 | — | +2.4 | −28% | +4.6% | — | −27% |
| CONDUCT | 742 | 24 | DUT 0.5 mg | Tamsulosin 0.4 mg | — | −3.6 a | — | −5.4 | — | — | — | — | — | — | — | — |
Related posts:
The Epidemiology of Benign Prostatic Hyperplasia Associated with Lower Urinary Tract Symptoms
Diagnostic Work-Up of Lower Urinary Tract Symptoms
Alpha-blockers for the Treatment of Benign Prostatic Hyperplasia
Bipolar, Monopolar, Photovaporization of the Prostate, or Holmium Laser Enucleation of the Prostate
Robotic-Assisted Simple Prostatectomy
Sexual Side Effects of Medical and Surgical Benign Prostatic Hyperplasia Treatments
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