Abstract
With age, men experience an increase in the volume of prostrate stroma (histologically diagnosed as benign prostatic hyperplasia (BPH); static component), and an increase in the alpha-1 adrenergic receptors in the prostate stroma (dynamic component). Either or both of these changes in synergy can result in lower urinary tract symptoms. 5-Alpha reductase inhibitors (5αRIs) block the conversion of testosterone to dihydrotestosterone (DHT) and thus limit prostate stroma growth. Regardless of initial prostate volume, consistent use of 5αRIs can reduce prostate volume by as much as 25% over the initial 12 months through prostatic epithelial cell apoptosis. 5αRI therapy prevents progression of BPH: treatment with 5αRI monotherapy is associated with significant reductions in the risk of acute urinary retention, the risk of surgical intervention for BPH, and the risk for any clinical progression of BPH. Several studies have demonstrated no significant differences between long-term treatment of BPH with finasteride versus dutasteride regarding changes in symptom scores, maximum urinary flow rate, postvoid residual volume, prostate volume, or prostate specific antigen (PSA) value; however, a lower incidence of sexual side effects may occur with finasteride compared with dutasteride. Combination therapy with a 5αRI and an alpha-1 adrenergic receptor blocker improves symptom scores and prevents the clinical progression of BPH better than either monotherapy; and improves maximum urinary flow rate, decreases risk of acute urinary retention, and decreases risk of invasive therapy for BPH better than alpha-1 adrenergic receptor blocker monotherapy. These benefits seem to be greatest for men with higher initial PSA and greater initial prostate volume. Additional indications for 5αRIs in the treatment of prostatic-origin hematuria and hemorrhage after transurethral resection of the prostate, as well as in the prevention and treatment of prostate cancer require further study.
Keywords
Benign prostatic hyperplasia, 5-Alpha reductase inhibitors, Finasteride, Dutasteride, Pharmacotherapy, Testosterone, Dihydrotestosterone
Mechanism of Action
Testosterone and Dihydrotestosterone
Androgens are steroid molecules composed of 19 carbons and either a keto group (dehydroepiandrosterone and androstenedione) or a hydroxyl group (testosterone and dihydrotestosterone (DHT)) at carbon 17. Testosterone, the most abundant serum androgen in men, is intracellularized and converted by the enzyme 5-alpha reductase to DHT, a ligand with 2–5 times greater binding affinity for the androgen receptor (AR) and with approximately 10 times greater potency for AR transactivation than testosterone [ ]. The resulting DHT-AR complex then translocates from the cytosol to the nucleus to induce transcription of androgen receptor-regulated genes (ARRGs). Through activated transcription of ARRGs, DHT is responsible for in utero male differentiation of the urogenital sinus into the urachus, part of the bladder, Cowper’s glands, the prostatic urethra, and the prostate gland; the urethral folds into the penile urethra; the genital tubercle into the penis; and the genital swellings into the scrotum; as well as pubertal growth of facial and body hair [ ]. Dysregulation of DHT manifests in such disease processes as acne, hirsutism, male pattern baldness, benign prostatic hyperplasia (BPH), and prostate cancer [ ].
5-Alpha Reductase Enzyme Family
The 5-alpha reductase enzyme family is responsible for the conversion of testosterone to DHT. With cofactor nicotinamide adenine dinucleotide phosphate (NADPH), isoenzymes of the 5-alpha reductase enzyme family catalyze an irreversible break of the double bond between carbons 4 and 5 of the testosterone molecule resulting in conversion to the DHT molecule. The 5-alpha reductase enzyme family is comprised of 3 subfamilies and 5 isoenzyme members: 5 alpha reductase-1 (5αR1; subfamily a), 5 alpha reductase-2 (5αR2; subfamily a), 5 alpha reductase-3 (5αR3; subfamily b), GPSN2 (subfamily c), and GPSN2L (subfamily c) [ ]. Within a given species, the 5αR1 (259 amino acids, 29.5 kDa molecular weight; encoded on chromosome 5p15) and 5αR2 (254 amino acids, 28.4 kDa molecular weight; encoded on chromosome 2p23) isoenzymes share a mean amino acid sequence homology of 47% [ ]. The 5αR1 and 5αR2 isoenzymes are both found embedded in a membrane lipid bilayer, attributable to a high content of hydrophobic amino acids. 5αR3 (318 amino acids; encoded on chromosome 4q12), GPSN2 (308 amino acids; encoded on chromosome 19p13.12), and GPSN2L (363 amino acids; encoded on chromosome 4q13.1) share a more limited degree of amino acid sequence homology [ ]. The expression of the isoenzymes varies by stage of human development and tissue type, and can exhibit interindividual and intraindividual expression heterogeneity [ ]. The most abundant isoenzymes in the prostate belong to subfamily a: 5αR2 and 5αR1. 5αR2 is more abundant and is predominantly expressed in the cytosol of stromal and basal prostate cells, whereas 5αR1 is predominantly expressed in the nucleus of prostate epithelial cells [ ]. In BPH, the histologic diagnosis referring to proliferation of benign smooth muscle and epithelial cells within the prostatic transition zone [ ], both the 5αR2 and 5αR1 isoenzymes are overexpressed [ ], although 5αR2 is more highly concentrated [ ]. Compared to benign and BPH prostate cells, increased expression of 5αR1 and decreased expression of 5αR2 have been demonstrated in prostate cancer cells [ ]. Studies have also shown an increase in 5αR1 and 5αR2 in localized high-grade compared to localized low-grade prostate cancer. Furthermore, a significant decrease in 5αR1 and a significant increase in 5αR2 have been identified in BPH compared to benign tissue adjacent to prostate cancer [ ]. In both androgen-stimulated and castrate recurrent prostate cancer cells, an increased expression of 5αR3 in the cytosol compared to benign prostate cells has also been described [ ].
Rationale for 5-Alpha Reductase Inhibition in BPH
With age, men experience an increase in the volume of prostrate stroma (histologically diagnosed as BPH; static component), and an increase in the alpha-1 adrenergic receptors in the prostate stroma (dynamic component). Either or both of these changes in synergy can result in lower urinary tract symptoms. Alpha-1 adrenergic receptors mediate smooth muscle contraction. The increased density of alpha-1 subtype a adrenergic receptors in the prostate stroma leads to increased muscle tone in the prostate and bladder neck that can restrict urine flow. Inhibitors of the alpha-1 subtype a adrenergic receptor relax the smooth muscle of the prostate and bladder neck potentially resulting in improved voiding, and the smooth muscle of the seminal vesicles and vas deferens potentially also resulting in retrograde ejaculation. Growth of the prostate stroma into the bladder, bladder neck, and prostatic urethra lumen can mechanically obstruct urine flow. Inhibitors of the 5-alpha reductase enzyme family block the conversion of testosterone to DHT and thus limit prostate stroma growth. Regardless of initial prostate volume, consistent use of 5αRIs can reduce prostate volume by as much as 17%–25% over the initial 12 months through prostatic epithelial cell apoptosis concentrated in the periurethral prostatic tissue [ ].
5-Alpha Reductase Inhibitors
5-Alpha reductase inhibitors (5αRIs) may act by one of three mechanisms: as a competitor of the substrate, as a competitor of the NADPH cofactor and substrate, or as a noncompetitor with the 5αR-NADP + complex [ ]. The types of inhibitors most widely studied may be classified as either steroidal (which mimic the natural substrate of 5αR, testosterone) or nonsteroidal. 4-Azosteroids are 3-oxo 5-alpha steroids with a nitrogen atom bonded to carbon 4. Members of this class of steroids act as competitive substrates of the 5αR isoenzymes, and include United States Food and Drug Administration (FDA)-approved drugs for the treatment of BPH such as finasteride and dutasteride [ ].
Finasteride
Finasteride, the first 5αRI approved for the treatment of BPH (5 mg po qday) and male pattern baldness (1 mg po qday), is a synthetic 4-azosteroid that acts as a potent competitive inhibitor of 5αR2 [IC 50 = 69 nM] and a less potent competitive inhibitor of 5αR1 [IC 50 = 360 nM] [ , ]. Finasteride also competitively inhibits 5αR3 [IC 50 = 17.4 nM] [ ]. The half-life of finasteride is 6–8 h [ ]. Mean serum DHT concentration has been shown to decrease by 75% after 6 months of treatment, whereas intraprostatic DHT concentration has been shown to decrease by 85% after 7 days of treatment, and by 68% after 6 months of treatment in men with BPH [ , , ].
Dutasteride
Dutasteride, the second 5αRI approved for the treatment of BPH (0.5 mg po qday), is a synthetic 4-azosteroid that acts as a potent competitive inhibitor of both 5αR1 [IC 50 = 7 nM] and 5αR2 [IC 50 = 6 nM]. In vitro studies have demonstrated that dutasteride also competitively inhibits 5αR3 [IC 50 = 0.33 nM] [ ]. The half-life of dutasteride is 5 weeks [ ]. Mean serum DHT concentration has been shown to decrease by 94.7% after 6 months of treatment in men with BPH and 89.7% after 4 months of treatment in men with prostate cancer [ , ]. Intraprostatic DHT concentration has been shown to decrease by 94% after 3 months of treatment in men with BPH; whereas, intraprostatic DHT concentration has been shown to decrease by 97% after 6–10 weeks of treatment and by 93.1% after 4 months of treatment in men with prostate cancer [ ].
5-ARI for the Treatment of BPH
Indications for Treatment of BPH With 5-ARI
Approximately 13% of males by age 50 years, and approximately 42% of males by age 80 years demonstrate clinical changes consistent with BPH [ ]. Depending on the degree of disease progression, BPH may be associated with varying degrees of lower urinary tract symptoms. BPH does not progress in all patients: of BPH patients with baseline moderate lower urinary tract symptoms, as many as 46.1% demonstrate no change in their symptoms and 12.7% demonstrate improvement in their symptoms after 4 years; and of BPH patients with baseline severe lower urinary tract symptoms, as many as 37.9% demonstrate no change in their symptoms and 22.7% demonstrate improvement in their symptoms after 4 years [ ]. The risk of BPH progression to worse lower urinary tract symptoms, development of urinary retention, and need for surgical intervention is higher in men of older age, higher initial prostate specific antigen (PSA), larger initial prostate size, lower urinary flow rates, greater post void residual urine volume, and more severe lower urinary tract symptoms [ , ]. The pharmacologic treatment goals for BPH include alleviation of bothersome lower urinary tract symptoms resulting from prostate enlargement; minimization of disease progression and need for surgical intervention; and prevention of complications of BPH including but not limited to urinary tract infection, urinary retention, and renal insufficiency. For the patient who presents with nonsuspicious prostate enlargement and minimal bother from lower urinary tract symptoms following appropriate history, physical, and diagnostic evaluation, reassurance is recommended. For the patient with nonsuspicious prostate enlargement and bothersome lower urinary tract symptoms, a shared decision-making process between the physician and the patient should guide treatment choice. For these patients, if behavioral modification results in insufficient lower urinary tract symptom improvement, pharmacologic treatment may be warranted. According to the 2011 update of the American Urologic Association (AUA) guidelines on BPH management, 5αRI therapy is an appropriate and effective treatment for men with lower urinary tract symptoms secondary to BPH and prostate enlargement as demonstrated by serum PSA, digital rectal exam, or transrectal ultrasound of the prostate. After initiation of 5αRI therapy, assessment of treatment response is recommended at an interval of at least 3 months. If treatment with a 5αRI results in sufficient lower urinary tract symptom improvement, annual re-evaluation is recommended [ ].
Clinical Effects of BPH Treatment With 5-ARI
Treatment with 5αRIs is associated with a likely clinically insignificant 12%–25% increase in serum testosterone [ ]. Furthermore, treatment with a 5αRI for a duration of 12 months is associated with a decrease in total serum PSA by approximately 50%: mean reduction from baseline PSA of 38.9% after 3 months and 47.7% after 12 months with finasteride therapy, mean reduction from baseline PSA of 40.3% after 3 months and 49.5% after 12 months with dutasteride therapy [ ]. Of note, the effect on the serum PSA level is similar after 12 months of treatment with finasteride 1 mg po qday for male pattern baldness as it is after 12 months of treatment with finasteride 5 mg po qday for BPH. For patients who remain on 5αRI therapy, this reduction in PSA must be taken into account when assessing the PSA trend for a given patient. Some experts recommend adjustment of the PSA value by a multiplicative factor of 2 post 5αRI treatment [ ]. Regardless of initial prostate volume, prostate volume can decrease by as much as 17%–25% over the initial 12 months of 5αRI treatment through prostatic epithelial cell apoptosis concentrated in the periurethral prostatic tissue [ ].
While lower urinary tract symptom improvement and side effects may be experienced within several weeks of initiation of 5αRI therapy, appreciable changes in prostate size, and associated improvements in lower urinary tract symptoms are typically achieved after 6–12 months of treatment [ , ]. The Proscar® Long-term Efficacy and Safety Study (PLESS) was a randomized double-blind placebo-controlled study assessing the safety and efficacy of daily oral therapy with finasteride over a 4-year period in men with symptomatic BPH, enlarged prostates, and no evidence of prostate cancer. In the PLESS, 5αRI therapy was demonstrated to be effective in decreasing prostate volume, and improving lower urinary tract symptoms and urinary flow rate in men with a baseline PSA ≥ 1.4 ng/mL and a baseline prostate volume > 40 g [ , , ]. Furthermore, a subset analysis from the Medical Therapy of Prostate Symptoms (MTOPS) trial demonstrated that finasteride treatment was associated with a significant decrease in lower urinary tract symptoms reported on the American Urologic Association Symptom Score (AUASS), a significant decrease in prostate volume, a significant increase in maximum urinary flow rate, and a significant increase in the cumulative percentage of patients without clinical progression of BPH compared to placebo treatment in men with a baseline prostate volume ≥ 30 g, but not for men with a baseline prostate volume < 30 g [ ].
The Combination of Avodart and Tamsulosin (CombAT) trial further demonstrated that dutasteride treatment can increase urinary flow rate by approximately 10%, but dutasteride generally required 12–18 months of treatment to achieve the same effect as tamsulosin, an alpha-1 adrenergic receptor blocker [ ]. The North American and International Phase III Finasteride trial demonstrated that 6-year treatment of BPH improved mean maximal urinary flow rate by 2.9 mL/s and mean quasi-AUASS by 4.0 points [ ]. MTOPS demonstrated that 5αRI therapy prevents progression of BPH: treatment with finasteride alone was associated with a 68% reduction in the risk of acute urinary retention, a 64% reduction in the risk of surgical intervention for BPH, and a 34% reduction in the risk for any clinical progression of BPH with a mean follow-up of 4.5 years [ ]. Of further note, there was no significant difference in the risk reduction for any clinical progression of BPH between 5αRI therapy alone (34%) and alpha-1 adrenergic receptor blocker therapy alone (39%), and alpha-1 adrenergic receptor blocker therapy alone did not result in a significant risk reduction in acute urinary retention or surgical intervention for BPH compared to placebo [ ]. 5αRI therapy has not been shown to reduce the risk of urinary tract infection, urinary incontinence, or renal insufficiency [ ].
Finasteride Versus Dutasteride for the Treatment of BPH
The Enlarged Prostate International Comparator Study (EPICS) was a multicenter randomized double-blind study comparing once daily therapy with finasteride 5 mg versus dutasteride 0.5 mg in men > 50 years of age with a clinical diagnosis of BPH. Subjects were first treated with 4 weeks of placebo, then were randomized to the finasteride or dutasteride treatment for 48 weeks, after which subjects were given the option to participate in a 24-month open label study of dutasteride treatment. No significant differences between finasteride therapy and dutasteride therapy were noted with regard to reduction of prostate volume, change in maximum urinary flow rate, changes in AUASS, or in adverse events. Therefore, it was concluded that finasteride and dutasteride were of similar clinical effectiveness for the treatment of BPH in men with an enlarged prostate when administered for 12 months [ ].
A single-center retrospective study of men treated with either finasteride or dutasteride monotherapy for BPH over 5 years found maintenance of therapy to be 57.4% for the finasteride group and 42.5% for the dutasteride group at 5 years. In this patient population, changes in International Prostate Symptom Score (IPSS), maximum urinary flow rate, postvoid residual volume, prostate volume, and PSA value were found to be similar for men in the finasteride and dutasteride groups [ ]. Both comparative studies suggest that 5αR2 contributes more to the clinical development of BPH as inhibition of both 5αR1 and 5αR2 by dutasteride does not seem to offer additional benefit compared to inhibition of mostly 5αR2 by finasteride.
Sexual Side Effects of 5-Alpha Reductase Inhibitor Use
Sexual side effects of 5αRI therapy have been described, but the approximate incidence of these sexual side effects is low: < 5% erectile dysfunction, 4% gynecomastia, < 4% decreased libido, and < 3% ejaculatory dysfunction. Among other variables, self-reported history of sexual dysfunction and sexual adverse events during treatment with finasteride were studied in the PLESS [ ]. 46% of subjects in both the treatment arm and the placebo arm self-reported a history of sexual dysfunction at the time of study screening. In the first year of the trial, 15% of subjects treated with finasteride and 7% of subjects treated with placebo reported treatment-related sexual adverse events. During the second through fourth years of the study, 7% of subjects treated with finasteride and 7% of subjects treated with placebo reported new treatment-related sexual adverse events. Of note, men with and without a history of sexual dysfunction had similar reports of treatment-related sexual adverse events. While continuing treatment, resolution of sexual side effects was achieved for 12% of subjects treated with finasteride and 19% of subjects treated with placebo. For the 4% of subjects treated with finasteride and the 2% of subjects treated with placebo who discontinued the study on account of sexual adverse events, resolution of sexual side effects was achieved after discontinuation of therapy for 50% and 41% of affected subjects, respectively [ ]. The PLESS therefore demonstrated that sexual side effects of 5αRI therapy are uncommon after the first year of therapy, and appear to be reversible with discontinuation of treatment for most patients. Similarly, several long-term studies of finasteride therapy for BPH demonstrated a low incidence of treatment-related sexual adverse events during the first year of treatment, which further declined during subsequent years of treatment [ , ]. In a review of placebo-controlled studies of 5αRI treatment for durations of 6 months to 4.5 years, it was found that sexual adverse events may be prolonged for a subset of patients. In the reviewed studies, treatment with finasteride compared to placebo was associated with a respective incidence range of 3.0%–15.8% versus 1.7%–6.3% for erectile dysfunction, 0.2%–7.7% versus 0.1%–1.7% for ejaculatory dysfunction, and 2.4%–18% versus 1.0%–6.3% for decreased libido; whereas, treatment with dutasteride compared to placebo was associated with a respective incidence range of 1.3%–11.0% versus 1.2%–6.0% for erectile dysfunction, 0.3%–3.0% versus 0.0%–0.1% for ejaculatory dysfunction, and 0.5%–6.0% versus 0.3%–3.0% for decreased libido [ ].
Comparative studies of finasteride and dutasteride have also reported on sexual side effects of 5αRI therapy. In a single-center retrospective analysis of men treated with either finasteride or dutasteride monotherapy for BPH over 5 years, maintenance of therapy was 57.4% for the finasteride group and 42.5% for the dutasteride group at 5 years. In this patient population, finasteride and dutasteride were found to have similar effectiveness in treating BPH, as measured by several clinical outcomes and IPSS. However, the incidence of sexual side effects resulting in discontinuation of therapy was significantly higher for dutasteride treatment compared to finasteride treatment: 5.1% versus 2.1% erectile dysfunction, 2.4% versus 1.8% ejaculatory dysfunction, 2.7% versus 1.4% decreased libido, respectively. Furthermore, a significantly higher self-reported incidence of breast tenderness or enlargement was found with dutasteride treatment (3.5%) compared to finasteride treatment (1.2%) [ ].
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