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PubMed2005

[Effect of dutasteride on reduction of plasma DHT following finasteride therapy in patients with benign prostatic hyperplasia].

INTRODUCTION: Dihydrotestosterone (DHT) is a steroid hormone derived from testosterone, by the action of two distinct isoenzymes (type 1 and 2) of 5-alpha-reductase. Dutasteride is a specific selective inhibitor of the two isoenzymes, while finasteride is a selective inhibitor of type 2 -alpha-reductase. The working hypothesis is that the double 5-alpha-reductase inhibition induced by dutasteride therapy for 6 weeks should induce a supplementary reduction of plasma DHT levels compared to a parallel patient group continuing finasteride therapy over the same period. MATERIALS AND METHODS: In this prospective, two-centre, double-blind study, 21 patients previously treated by finasteride 5 mg for benign prostatic hyperplasia (BPH) for at least 6 months were randomized to receive either dutasteride 0.5 mg, or finasteride 5 mg daily for 6 weeks. RESULTS: The mean relative variation of plasma DHT was 67.3% +/- 16.16% in the dutasteride group and 30.3% +/- 59.8% in the finasteride group. The reduction of DHT was numerically greater and more constant in the dutasteride group than in the finasteride group at 6 weeks; such a tendency was already observed after two weeks of treatment with dutasteride. Nevertheless, these differences were not statistically significant. Both medications were well tolerated and the only treatment-related adverse event (epigastric pain) was reported in the finasteride group. CONCLUSIONS: The working hypothesis was therefore not statistically confirmed. It is difficult to conclude whether this reflects poor patient compliance with long-term finasteride for BPH or variability of response in patients with good compliance with treatment.

Aged↗
PubMed2006

Effects of the dual 5 alpha-reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines.

BACKGROUND: The profound reduction in serum dihydrotestosterone (DHT) observed with the dual 5 alpha-reductase inhibitor (5ARI) dutasteride makes it an attractive agent for prostate cancer therapy. The objective of the current study was to determine whether dutasteride would induce apoptosis in a range of prostate epithelial cell lines and primary cultures. METHODS: Both human prostate androgen-sensitive cell lines (PwR-1E, PNT-2, LNCaP, and PC3[AR2]) and an androgen-independent cell line (PC-3) were grown to confluence. Primary epithelial cells extracted from fresh prostate cancer radical prostatectomy specimens also were grown to confluence under optimal conditions. Total cellular protein was extracted to confirm cytokeratin 18 and antihuman alpha-methylacyl-CoA racemase (AMACR) expression of the primary cells. Apoptosis was assessed by propidium iodide DNA staining and flow cytometry after 24 hours of culture in from 0 microM to 10 microM of dutasteride. RESULTS: Dutasteride induced a dose-dependent increase in apoptosis in the androgen-sensitive prostate cell lines PwR-1E, PNT-2, and LNCaP and in the androgen receptor-expressing PC3(AR2) cell line. However, there was no significant apoptosis noted in the parental PC-3 cells. Of 16 primary epithelial cultures that were treated, 7 cultures were induced to undergo apoptosis, and 9 cultures were unresponsive. All primary cultures were positive for cytokeratin 18 expression, confirming their epithelial phenotype. Responder epithelial cells were positive for AMACR expression. CONCLUSIONS: The results of the current study confirmed that dutasteride differentially induced apoptosis in a subset of prostate cell lines and primary prostate epithelial cells. Understanding the cellular phenotype may indicate susceptible cells.

Apoptosis↗
PubMed2006

Dutasteride improves objective and subjective disease measures in men with benign prostatic hyperplasia and modest or severe prostate enlargement.

PURPOSE: We determined whether the effect of dutasteride for benign prostatic hyperplasia is influenced by baseline prostate volume using data from 3 phase III clinical trials. MATERIALS AND METHODS: Patients randomized to dutasteride or placebo in the double-blind portion of the phase III studies were eligible to receive 0.5 mg dutasteride daily in a 2-year open label extension in dutasteride/dutasteride and placebo/dutasteride groups. Patients were prospectively stratified according to baseline prostate volume 30 to less than 40 and 40 cc or greater. RESULTS: In patients treated with dutasteride throughout the study (dutasteride/dutasteride group) the mean reduction in prostate volume from baseline to month 48 was 30.3% in those with a baseline prostate volume of 30 to less than 40 cc and 26.2% in those with a prostate volume of 40 cc or greater. Mean improvements in peak urinary flow from baseline to month 48 were 2.7 ml per second regardless of baseline prostate volume. Improvements in the American Urological Association symptom index score were 6.3 in men with a prostate volume of 30 to less than 40 cc and 6.5 in those with a prostate volume of 40 cc or greater. No significant relationships between treatment effect and baseline prostate volume were observed for these parameters. In dutasteride/dutasteride treated patients the risk of acute urinary retention was decreased by 60% in those with a prostate volume of 30 to less than 40 cc and 55% in those with a prostate volume of 40 cc or greater vs values in placebo/dutasteride treated patients (p = 0.036 and <0.001, respectively). The corresponding values for benign prostatic hyperplasia related surgery were 27% and 48% (p = 0.35 and <0.001, respectively). CONCLUSIONS: This analysis demonstrates that dutasteride significantly improves objective (prostate volume and peak urinary flow) and subjective (symptom scores) measures even in patients with only a slightly enlarged prostate (30 to less than 40 cc). The risks of acute urinary retention and benign prostatic hyperplasia related surgery were decreased regardless of baseline prostate volume.

Aged↗
PubMed2004

Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia.

OBJECTIVES: To assess the long-term safety and efficacy of dutasteride, a dual type 1 and type 2 5-alpha-reductase inhibitor, in the treatment of symptomatic benign prostatic hyperplasia and associated lower urinary tract symptoms. METHODS: Data from two Phase IIIa multicenter, randomized, placebo-controlled trials of 2-year duration plus a 2-year open-label extension were pooled and analyzed. The entry criteria included age 50 years old or older, clinical diagnosis of benign prostatic hyperplasia, prostate volume of 30 cm3 or greater, American Urological Association symptom score of 12 or greater, peak urinary flow rate of 15 mL/s or less, and prostate-specific antigen level of 1.5 ng/mL or greater but less than 10 ng/mL. RESULTS: A total of 2802 men were randomized into the double-blind phase of the two studies with 1908 patients (68%) completing the study. Of these, 1570 subjects were enrolled in the open-label phase, and 569 subjects received dutasteride for 48 months. Changes at the 48-month visit for dutasteride/dutasteride-treated subjects included improvement in prostate volume (-26.2%), American Urological Association Symptom Index (-6.1 points), and peak urinary flow rate (+2.8 mL/s). Changes for the placebo/dutasteride group included prostate volume (-20.7%), American Urological Association Symptom Index (-5.3 points), and peak urinary flow rate (+1.8 mL/s). Acute urinary retention and surgery occurred in a small percentage of subjects (less than 2% and less than 1%) in the open-label extension phase. Dutasteride was well tolerated with no statistically significant increase in drug-related adverse events during the open-label extension and no adverse laboratory trends. CONCLUSIONS: Dual inhibition of 5-alpha-reductase with dutasteride provided sustained efficacy in subjects with symptomatic benign prostatic hyperplasia treated for 48 months. Near-complete, long-term suppression of dihydrotestosterone (93% at 48 months) with dutasteride did not lead to an increase in adverse events compared with that reported in the 2-year period.

5-alpha Reductase Inhibitors↗
PubMed2006

Efficacy of neoadjuvant bicalutamide and dutasteride as a cytoreductive regimen before prostate brachytherapy.

OBJECTIVES: To evaluate the cytoreductive effectiveness of combined neoadjuvant bicalutamide and dutasteride before prostate brachytherapy for clinically localized prostate cancer. METHODS: From April 2003 to May 2005, 31 patients opted for cytoreduction with bicalutamide (50 mg daily) and dutasteride (0.5 mg daily). Before, and at 3 months (90 +/- 5 days) after, the initiation of medical therapy, all patients underwent a transrectal ultrasound volumetric study of the prostate gland, with ellipsoid volume determination of the prostate gland and transition zone. The variables analyzed included pretreatment and posttreatment prostate and transition zone volumes and changes in width, height, and length of the prostate gland and transition zone. A multivariate analysis was performed to identify predictors for prostate gland and transition zone volume reduction. RESULTS: Before the initiation of bicalutamide and dutasteride, the mean prostate volume was 54.3 cm3 by planimetric summation and 49.7 cm3 by ellipsoid volume calculation. After a 3-month course of combination medical therapy, the average prostate volume was 36.1 cm3 (33.6% reduction) and 32.5 cm3 (34.6% reduction) using the volumetric and ellipsoid volume determinations, respectively. Bicalutamide and dutasteride resulted in a 39.8% reduction in transition zone volume (20.8 cm3 versus 12.4 cm3). The prostate gland and transition zone dimensions (width, height, and length) decreased about 11.4% to 19.9%. CONCLUSIONS: The prostate gland and transition zone volume reductions after a 3-month course of neoadjuvant bicalutamide and dutasteride are comparable to previous reports of volume reduction using a luteinizing hormone-releasing hormone agonist with or without an antiandrogen.

5-alpha Reductase Inhibitors↗
PubMed2005

Chemoprevention using dutasteride: the REDUCE trial.

PURPOSE OF REVIEW: This article will review the design and rationale of the dutasteride prostate cancer chemoprevention trial known as the REDUCE trial (Reduction by Dutasteride of Prostate Cancer Events) in the context of the recently completed Prostate Cancer Prevention Trial. RECENT FINDINGS: The Prostate Cancer Prevention Trial used the 5alpha-reductase inhibitor finasteride to prevent prostate cancer in a prospective randomized trial. The trial demonstrated a nearly 25% reduction in the prevalence of prostate cancer compared with placebo. Finasteride is a type 2-specific 5alpha-reductase inhibitor, whereas dutasteride is an inhibitor of both type 1 and type 2 5alpha-reductase. Recent evidence suggests that there may be increased expression of the type 1 5alpha-reductase in prostate cancer versus benign prostate tissue making dutasteride an attractive agent to study. SUMMARY: Proof of principle has been demonstrated by the Prostate Cancer Prevention Trial that a chemoprevention strategy using a hormonal agent such as a 5alpha-reductase inhibitor can be effective. The REDUCE trial will use the dual 5alpha-reductase inhibitor dutasteride in a group of men identified at increased risk of developing prostate cancer to determine if this will be an effective chemoprevention strategy.

5-alpha Reductase Inhibitors↗
PubMed2004

Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial.

PURPOSE: Chemoprevention may significantly impact the natural history of prostate cancer. The most potent intraprostatic androgen, dihydrotestosterone, has a significant role in the pathophysiology of prostate cancer. It represents a biologically plausible target for chemoprevention through the inhibition of 5alpha-reductase isoenzymes. MATERIALS AND METHODS: The Reduction by Dutasteride of Prostate Cancer Events clinical trial is an international, multicenter, double-blind, placebo controlled chemoprevention study designed to determine if dutasteride 0.5 mg daily decreases the risk of biopsy detectable prostate cancer. A total of 8,000 men will be randomized to receive dutasteride or placebo for 4 years. Eligible men must be 50 to 75 years old, have a serum prostate specific antigen of 2.5 to 10 ng/ml (ages 50 to 60 years) or 3.0 to 10 ng/ml (older than 60 years). Men must have a negative 6 to 12 core biopsy within 6 months prior to enrollment. Repeat biopsies will be taken at 2 and 4 years. The rates of prostate cancer for each treatment group will be compared. Genetic and protein biomarkers of prostate cancer, and the effect of dutasteride on benign prostatic hyperplasia and prostatitis symptomatology and histopathology will also be assessed. RESULTS: Results remain to be determined. CONCLUSIONS: The study will examine the effects of the dual 5alpha-reductase inhibitor dutasteride on the natural history of prostate cancer in men at increased risk for this malignancy. It affords a unique opportunity to examine biomarkers and genetic linkage for prostate cancer, and assess a range of prostate health outcome measures.

5-alpha Reductase Inhibitors↗
PubMed2004

Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor.

Dihydrotestosterone (DHT) is the primary metabolite of testosterone in the prostate and skin. Testosterone is converted to DHT by 5alpha-reductase, which exists in two isoenzyme forms (types 1 and 2). DHT is associated with development of benign prostatic hyperplasia (BPH), and reduction in its level with 5alpha-reductase inhibitors improves the symptoms associated with BPH and reduces the risk of acute urinary retention and prostate surgery. A selective inhibitor of the type 2 isoenzyme (finasteride) has been shown to decrease serum DHT by about 70%. We hypothesized that inhibition of both isoenzymes with the dual inhibitor dutasteride would more effectively suppress serum DHT levels than selective inhibition of only the type 2 isoenzyme. A total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 +/- 1.2% with 5.0 mg dutasteride and 94.7 +/- 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 +/- 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo.

Androgen Antagonists↗
PubMed2006

Relationship among serum testosterone, sexual function, and response to treatment in men receiving dutasteride for benign prostatic hyperplasia.

CONTEXT: Although benign prostatic hyperplasia (BPH) is an androgen-dependent disorder, little is known regarding the influence of serum testosterone levels on sexual or prostate function or clinical response to dutasteride. OBJECTIVE: The objective of the study was to explore these relationships in a large cohort of men treated with dutasteride for BPH. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: Among 4254 men with BPH participating in 2-yr placebo-controlled dutasteride trials, 27% had a pretreatment serum testosterone less than 300 ng/dl. These 1162 men were divided into seven groups based on their serum testosterone level (<150, 150-174, 175-199, 200-224, 225-249, 250-274, and 275-299 ng/dl) and compared with men with normal baseline serum testosterone (BST; > or = 300 ng/dl). Questionnaires were used to assess sexual function, prostate-specific antigen (PSA), and prostate volume to assess androgenic stimulation of the prostate and the American Urological Association Symptom Index to assess clinical responses. RESULTS: Although lower BST was associated with increased sexual dysfunction, this increase was not seen until BST was less than 225 ng/dl. There was no decrease in baseline PSA and prostate volume at low BST levels. Dutasteride was effective at decreasing PSA and prostate volume and improving BPH symptoms at all BST levels. CONCLUSIONS: In men with BPH, the frequency of sexual dysfunction increases at serum testosterone concentrations less than 225 ng/dl. However, PSA and prostate volume were similar at all testosterone levels, explaining why BPH can occur in men that would otherwise be considered hypogonadal. The fact that dutasteride is also effective in men with normal and low testosterone levels suggests that the high levels of 5alpha-reductase and dihydrotestosterone in the prostate allow the development and progression of prostatic hyperplasia, even at low circulating testosterone levels.

Aged↗
PubMed2005

Dutasteride: a novel dual inhibitor of 5alpha-reductase for benign prostatic hyperplasia.

Dutasteride is a new dual 5alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia. It differs from finasteride as it inhibits both isoenzymes of 5alpha-reductase and results in near-complete suppression of serum dihydro-testosterone. Similar to finasteride, it reduces serum prostatic specific antigen by approximately 50% at 6months and total prostate volume by 25% in 2years. Randomised, placebo-controlled trials conducted over 2years have shown the efficacy of dutasteride in symptomatic relief, improvements in quality of life and peak urinary flow rate, and reduction of acute urinary retention events and the need for surgery. The main side effects are erectile dysfunction, decreased libido, gynaecomastia and ejaculation disorders. However, long-term usage for > 4years did not reveal increased new onset of sexual side effects. In addition, the combination of dutasteride and tamsulosin is well-tolerated and has the added advantage of rapid symptomatic relief. Finally, dutasteride has been shown to possess tumour regression properties invitro and its role in chemoprevention of prostate cancer will be confirmed in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2005

[Effect of dutasteride on reduction of intraoperative bleeding related to transurethral resection of the prostate].

OBJECTIVE: The pharmacological action of 5-alpha-reductase inhibitors (5-ARI) would reduce angiogenesis associated with benign prostatic hyperplasia (BPH), thereby decreasing peroperative bleeding during transurethral resection of the prostate (TURP). Dutasteride, a double inhibitor of 5-alpha-reductase iso-enzymes types 1 and 2, was not been previously studied in the context of reduction of peroperative bleeding related to TURP. MATERIAL AND METHODS: We conducted a multicentre, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy of dutasteride 0.5 mg per day, in peroperative bleeding related to TURP for BPH in patients over the age of 50 years with a prostatic volume greater than 30 cm3. Treatment was administered for 4 weeks before the operation. The primary endpoint was haemoglobin, expressed in grams, and expressed in relation to the weight of prostate resected, also expressed in grams. RESULTS: 59 patients were evaluated (32 treated with dutasteride and 27 treated with placebo). A significant difference in peroperative bleeding was observed between the dutasteride group (1.944 +/- 1.816 g of Hb/g of prostate resected) and the placebo group (1.401 +/- 1.021 g of Hb/g of prostate resected). Preoperative treatment was well tolerated. CONCLUSION: The working hypothesis of the study was not confirmed due to the low bleeding rate in the placebo group and the results suggest that a longer duration of treatment with dutasteride would reduce intraoperative and postoperative bleeding in TURP.

Aged↗
PubMed2006

The effects of the dual 5alpha-reductase inhibitor dutasteride on localized prostate cancer--results from a 4-month pre-radical prostatectomy study.

BACKGROUND: As dihydrotestosterone (DHT) is the most potent androgen in the prostate, inhibition of the 5alpha-reductase isoenzymes, which convert testosterone to DHT, could be an appropriate target for the treatment of prostate cancer. METHODS: Eighty-one men with clinically localized prostate cancer received daily dutasteride 3.5 or 0.5 mg, or no therapy for 4 months before radical prostatectomy. Histopathological assessments were conducted on prostatectomy specimens. RESULTS: Treatment with dutasteride was associated with reductions in serum and intraprostatic DHT of >or=90%, and a decrease in total prostate and tumor volumes. No effect of dutasteride was noted on Gleason grade. Histopathological effects on benign tissue were similar but less prominent than those seen with androgen ablation, whereas there was no significant difference in cancer histology among the groups. CONCLUSIONS: Dutasteride treatment results in similar but less marked changes compared with androgen ablation.

5-alpha Reductase Inhibitors↗
PubMed2005

The dual 5-alpha-reductase inhibitor dutasteride induces atrophic changes and decreases relative cancer volume in human prostate.

OBJECTIVES: To perform the first evaluation of the effects of the 5-alpha-reductase inhibitor class of drugs on cancer histopathologic features at radical prostatectomy in a placebo-controlled multicenter trial. METHODS: We analyzed prostatectomy slides in a blinded manner from 17 men treated with dutasteride, an inhibitor of types 1 and 2 isoenzymes of 5-alpha-reductase, and 18 men treated with placebo for 5 to 11 weeks before radical prostatectomy. The histopathologic features of benign epithelium, high-grade prostatic intraepithelial neoplasia, and cancer were recorded, and the treatment effect was scored. Digital imaging analysis was used to measure the stroma/epithelium ratio and epithelial height, as well as the nuclear area in cancer. RESULTS: In benign epithelium, treatment caused distinctive cytoarchitectural changes of atrophy and a decrease in the epithelial height (P = 0.053). The peripheral zone showed the most marked response to treatment. In cancer tissue, the tumor volume was significantly lower in the dutasteride-treated men than in the placebo-treated men (mean 15% versus 24%, respectively, P = 0.025), the percentage of atrophic epithelium was increased (P = 0.041), and the stroma/gland ratio was doubled (P = 0.046). The treatment alteration effect score was doubled (P = 0.055) and did not correlate with any Gleason score changes. CONCLUSIONS: After short-term dutasteride treatment, benign epithelium showed involution and epithelial shrinkage, and prostate cancer tissue demonstrated a decrease in epithelium relative to stroma. These findings indicate that dutasteride induces significant phenotypic alterations in both the benign and the neoplastic prostate, supportive of a chemopreventive or chemoactive role.

5-alpha Reductase Inhibitors↗
PubMed2006

Development of nomogram to predict acute urinary retention or surgical intervention, with or without dutasteride therapy, in men with benign prostatic hyperplasia.

OBJECTIVES: To develop a prediction model, or nomogram, that would predict the probability that a man with benign prostatic hyperplasia would experience acute urinary retention (AUR) or require surgical intervention (SI) within 2 years, with or without dutasteride therapy. METHODS: We modeled 4294 men treated in the Phase III dutasteride benign prostatic hyperplasia trials. These men were characterized at baseline by a number of parameters, including the American Urological Association Symptom Index, Benign Prostatic Hyperplasia Impact Index questionnaire, prior use of selective alpha1-blockers, prostate volume, prostate-specific antigen level, and maximal flow rate. Cox proportional hazards regression analysis was used to relate these baseline variables to their future probability of AUR/SI within 2 years. The nomogram was internally validated with bootstrapping to assess its discrimination and calibration. Discrimination was quantified as the concordance index. RESULTS: The nomogram appeared to be accurately calibrated and discriminating (concordance index 0.71, P <0.001). CONCLUSIONS: We constructed a nomogram for predicting the probability that a man would experience AUR or require SI within 2 years of benign prostatic hyperplasia diagnosis. At 24 months of follow-up, 7.4% of placebo patients and 3.7% of dutasteride patients had experienced AUR and/or SI, representing a 50% relative risk reduction and a 3.7% absolute risk reduction. For the greatest risk patient randomized to the Phase III dutasteride trial, the nomogram predicted a maximal risk of 27%, significantly greater than the median risk of the placebo-treated patients.

Acute Disease↗
PubMed2006

Efficacy and tolerability of the dual 5alpha-reductase inhibitor, dutasteride, in the treatment of benign prostatic hyperplasia in African-American men.

The efficacy and tolerability of dutasteride (0.5 mg daily for 2 years) in African-Americans (n=161), compared with Caucasians (n=3961), was assessed in a post hoc analysis of data from three Phase III clinical trials. Dutasteride significantly reduced serum dihydrotestosterone levels by >90% and significantly improved subjective (symptom score) and objective (prostate volume, peak urinary flow rate, risk of benign prostatic hyperplasia-related surgery and acute urinary retention) outcomes in both African-Americans and Caucasians. For all efficacy measures, there was no statistically significant treatment-by-race interaction and dutasteride was well tolerated in both racial groups. Therefore, dutasteride demonstrated similar efficacy and safety profiles in African-Americans and Caucasians.

5-alpha Reductase Inhibitors↗
PubMed2005

Effect of dutasteride therapy on Doppler US evaluation of prostate: preliminary results.

PURPOSE: To prospectively determine the effect of short-term therapy with dutasteride on the suppression of Doppler ultrasonographic (US) signal in benign prostate tissue and thus on improvement in the depiction of prostate cancer with Doppler US-guided core-needle biopsy. MATERIALS AND METHODS: After institutional review board approval and informed consent were obtained as part of this HIPAA-compliant study, 11 men (age range, 59-77 years) were evaluated with gray-scale, color, and power Doppler US at baseline and weekly for up to 3 weeks while taking 0.5 mg of dutasteride per day. Flow intensity in the periurethral, transition, and peripheral zones was subjectively scored by using a four-point scale. The Wilcoxon matched-pairs signed-ranks test was used to compare pre- and posttherapy scores. After flow was reduced to "diminished" or "none" with at least a 1-score difference on the four-point scale, up to four targeted cores were obtained from areas of persistent flow within the peripheral zone, followed by laterally directed sextant biopsy. RESULTS: Doppler US flow suppression occurred in 11 of 11 patients after 1 week of dutasteride therapy (P < .01). Further suppression was noted after 2 weeks in eight of 10 patients (P = .04) and after 3 weeks in two of two patients. Biopsy was performed after 1 (n = 1), 2 (n = 8), or 3 (n = 2) weeks of therapy. Flow suppression was greatest in the peripheral zones (mean decrease: 0.64 and 0.76 after weeks 1 and 2, respectively) and least in the periurethral zones (mean decrease: 0.30 after 1 week). Cancer was detected in eight (20%) of 40 targeted cores and in five (8%) of 66 sextant cores. Four patients had cancer at targeted biopsy, and three of these four patients had cancer at sextant biopsy. In the four men with cancer, targeted cores were 5.9 times more likely to be positive (P = .027). Selective suppression of flow in benign tissue was observed in two of the four men with cancer. CONCLUSION: Short-term dutasteride therapy reduces Doppler US flow in the prostate and may improve depiction of hypervascular cancer.

Aged↗
PubMed2005

Pharmacogenetic analysis of human steroid 5 alpha reductase type II: comparison of finasteride and dutasteride.

Human steroid 5 alpha-reductase type II is a prostate-specific, membrane-associated enzyme that catalyzes the conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate gland. Genetic variants of this enzyme have been associated with both the development and the progression of prostate cancer. Both finasteride and dutasteride are competitive inhibitors of the type II steroid 5 alpha-reductase that have been effectively used for the treatment of benign prostatic hyperplasia. Finasteride has also been successfully utilized for prostate cancer chemoprevention. We here investigate 5 alpha-reductase inhibition assays in vitro to measure the effect of incubation time on the apparent inhibition constant (Ki) for both constitutional and somatic (prostate cancer) enzyme variants. Our systematic pharmacogenetic analysis shows that both finasteride and dutasteride are slow, time-dependent inhibitors of steroid 5 alpha-reductase type II, and that the inhibition kinetics depend on the 5 alpha-reductase genotype. We also show that, overall, dutasteride is a more efficient steroid 5 alpha-reductase inhibitor than finasteride. Based on our data, we are able to map areas of the enzyme that are responsible for this time-dependent inhibition for either (or both) enzyme inhibitor(s). This comprehensive pharmacogenetic analysis of steroid 5 alpha-reductase variants unveiled significant pharmacogenetic variation for both finasteride and dutasteride and thus should be taken into account when designing protocols for treatment and/or chemoprevention of prostatic diseases with either one of these 5 alpha-reductase inhibitors since there is considerable pharmacogenetic variation for both drugs.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2003

Dutasteride: a new 5-alpha reductase inhibitor for men with lower urinary tract symptoms secondary to benign prostatic hyperplasia.

Dutasteride is a new 5-alpha reductase inhibitor for the treatment of men with moderate to severe lower urinary tract symptoms secondary to benign prostatic hyperplasia. It has been available in the UK since March 2003. It is a competitive inhibitor of both type I and type II isoforms of the 5-alpha reductase enzyme that converts testosterone to the more potent androgen, dihydrotestosterone. Randomised controlled studies have shown dutasteride to be statistically more effective than placebo in reducing lower urinary tract symptoms and increasing maximum urinary flow rates. This is a consequence of a reduction in serum dihydrotestosterone and hormone dependent prostate volume. Dutasteride has also been shown to decrease the absolute risk of urinary retention and the need for prostate-related surgery when compared to placebo taken over a 24-month period. In this review article we discuss the pharmacology and clinical effects of dutasteride, a new dual-acting 5-alpha reductase inhibitor.

5-alpha Reductase Inhibitors↗