DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.

Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men.

Circulating androgen levels are often used as indicators of physiological or pathological conditions. More than half of the variance for circulating androgen levels is thought to be genetically influenced. A genome-wide association study (GWAS) has identified two loci, SHBG at 17p13 and FAM9B at Xp22, for serum testosterone (T) levels; however, these explain only a small fraction of inter-individual variability. To identify additional genetic determinants of androgen levels, a GWAS of baseline serum T and dihydrotestosterone (DHT) levels was conducted in 3225 men of European ancestry from the REduction by DUtasteride of Prostate Cancer Events (REDUCE) study. Cross-validation was used to confirm the observed associations between the drug (n = 1581) and placebo (n = 1644) groups of REDUCE. In addition to confirming the associations of two known loci with serum T levels (rs727428 in SHBG: P = 1.26 × 10(-12); rs5934505 in FAM9B: P = 1.61 × 10(-8)), we identified a new locus, JMJD1C at 10q21 that was associated with serum T levels at a genome-wide significance level (rs10822184: P = 1.12 × 10(-8)). We also observed that the SHBG locus was associated with serum DHT levels (rs727428: P = 1.47 × 10(-11)). Moreover, two additional variants in SHBG [rs72829446, in strong linkage equilibrium with the missense variant D356N (rs6259), and rs1799941] were also independently associated with circulating androgen levels in a statistical scale. These three loci (JMJD1C, SHBG and FAM9B) were estimated to account for ~5.3 and 4.1% of the variance of serum T and DHT levels. Our findings may provide new insights into the regulation of circulating androgens and potential targets for androgen-based therapy.

A comparison of Bayesian and frequentist approaches to incorporating external information for the prediction of prostate cancer risk.

We present the most comprehensive comparison to date of the predictive benefit of genetics in addition to currently used clinical variables, using genotype data for 33 single-nucleotide polymorphisms (SNPs) in 1,547 Caucasian men from the placebo arm of the REduction by DUtasteride of prostate Cancer Events (REDUCE®) trial. Moreover, we conducted a detailed comparison of three techniques for incorporating genetics into clinical risk prediction. The first method was a standard logistic regression model, which included separate terms for the clinical covariates and for each of the genetic markers. This approach ignores a substantial amount of external information concerning effect sizes for these Genome Wide Association Study (GWAS)-replicated SNPs. The second and third methods investigated two possible approaches to incorporating meta-analysed external SNP effect estimates - one via a weighted PCa 'risk' score based solely on the meta analysis estimates, and the other incorporating both the current and prior data via informative priors in a Bayesian logistic regression model. All methods demonstrated a slight improvement in predictive performance upon incorporation of genetics. The two methods that incorporated external information showed the greatest receiver-operating-characteristic AUCs increase from 0.61 to 0.64. The value of our methods comparison is likely to lie in observations of performance similarities, rather than difference, between three approaches of very different resource requirements. The two methods that included external information performed best, but only marginally despite substantial differences in complexity.

Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial.

BACKGROUND: We aimed to investigate the safety and efficacy of dutasteride, a 5α-reductase inhibitor, on prostate cancer progression in men with low-risk disease who chose to be followed up with active surveillance. METHODS: In our 3 year, randomised, double-blind, placebo-controlled study, undertaken at 65 academic medical centres or outpatient clinics in North America, we enrolled men aged 48-82 years who had low-volume, Gleason score 5-6 prostate cancer and had chosen to be followed up with active surveillance. We randomly allocated participants in a one-to-one ratio, stratified by site and in block sizes of four, to receive once-daily dutasteride 0·5 mg or matching placebo. Participants were followed up for 3 years, with 12-core prostate biopsy samples obtained after 18 months and 3 years. The primary endpoint was time to prostate cancer progression, defined as the number of days between the start of study treatment and the earlier of either pathological progression (in patients with ≥1 biopsy assessment after baseline) or therapeutic progression (start of medical therapy). This trial is registered with ClinicalTrials.gov, number NCT00363311. FINDINGS: Between Aug 10, 2006, and March 26, 2007, we randomly allocated 302 participants, of whom 289 (96%) had at least one biopsy procedure after baseline and were included in the primary analysis. By 3 years, 54 (38%) of 144 men in the dutasteride group and 70 (48%) of 145 controls had prostate cancer progression (pathological or therapeutic; hazard ratio 0·62, 95% CI 0·43-0·89; p=0·009). Incidence of adverse events was much the same between treatment groups. 35 (24%) men in the dutasteride group and 23 (15%) controls had sexual adverse events or breast enlargement or tenderness. Eight (5%) men in the dutasteride group and seven (5%) controls had cardiovascular adverse events, but there were no prostate cancer-related deaths or instances of metastatic disease. INTERPRETATION: Dutasteride could provide a beneficial adjunct to active surveillance for men with low-risk prostate cancer. FUNDING: GlaxoSmithKline.

Effect of dutasteride on the risk of prostate cancer.

BACKGROUND: We conducted a study to determine whether dutasteride reduces the risk of incident prostate cancer, as detected on biopsy, among men who are at increased risk for the disease. METHODS: In this 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, we compared dutasteride, at a dose of 0.5 mg daily, with placebo. Men were eligible for inclusion in the study if they were 50 to 75 years of age, had a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng per milliliter, and had had one negative prostate biopsy (6 to 12 cores) within 6 months before enrollment. Subjects underwent a 10-core transrectal ultrasound-guided biopsy at 2 and 4 years. RESULTS: Among 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P<0.001). Overall, in years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 tumors with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (P=0.81). During years 3 and 4, there were 12 tumors with a Gleason score of 8 to 10 in the dutasteride group, as compared with only 1 in the placebo group (P=0.003). Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in our study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P=0.03). CONCLUSIONS: Over the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00056407.)

Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study.

OBJECTIVES: To determine if dutasteride-treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. To analyse whether the use of treatment-specific criteria for repeat biopsy maintains the usefulness of prostate-specific antigen (PSA) level for detecting high grade cancers. PATIENTS AND METHODS: The REDUCE study was a randomized, double-blind, placebo-controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy-detectable prostate cancer in men with a previous negative biopsy. The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds. RESULTS: Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8-10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8-10 cancers would have been missed in the placebo group. In both groups, the incidence of Gleason 7 and Gleason 8-10 cancers generally increased with greater rises in PSA. Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7-10 cancers in men treated with dutasteride vs placebo. Men with Gleason 7 and Gleason 8-10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds. CONCLUSION: Using treatment-specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8-10) or higher than (Gleason 7-10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.

Dutasteride reduces prostatitis symptoms compared with placebo in men enrolled in the REDUCE study.

PURPOSE: Men at risk for prostate cancer may concurrently experience chronic prostatitis or pelvic pain. We evaluated the effect of dutasteride on prostatitis-like symptoms in the REDUCE study population. MATERIALS AND METHODS: REDUCE was a 4-year, randomized, double-blind, placebo controlled study of prostate cancer risk reduction with 0.5 mg dutasteride vs placebo in men 50 to 75 years old with prostate specific antigen 2.5 to 10 ng/ml and a negative prostate biopsy in the previous 6 months. In this analysis we investigated change from baseline in Chronic Prostatitis Symptom Index in men with prostatitis-like pain (Chronic Prostatitis Symptom Index pain subscore 5 or greater) and prostatitis-like syndrome (perineal or ejaculatory pain plus Chronic Prostatitis Symptom Index pain subscore 4 or greater), the proportion of subjects with at least a moderate Chronic Prostatitis Symptom Index response (6-unit or greater improvement) and reports of new onset clinical prostatitis. RESULTS: Of 5,379 men with a total baseline Chronic Prostatitis Symptom Index score 678 (12.6%) had prostatitis-like pain and 427 (7.9%) had prostatitis-like syndrome. Chronic Prostatitis Symptom Index total score decreased significantly at 48 months in the dutasteride group vs placebo in men with prostatitis-like pain (p <0.0001) and with prostatitis-like syndrome (t test p = 0.03). There were significantly more Chronic Prostatitis Symptom Index responders with dutasteride vs placebo in the prostatitis-like pain (49% vs 37%, respectively, p = 0.0033) and prostatitis-like syndrome (46% vs 35%, Fisher's exact test p = 0.0265) subgroups. Prostatitis was reported as an adverse event by significantly more men randomized to placebo (3.6%) than to dutasteride (2.5%, p = 0.003). CONCLUSIONS: Long-term dutasteride therapy resulted in improvement in prostatitis related symptoms in older men with an increased prostate specific antigen.

The effect of dutasteride on the usefulness of prostate specific antigen for the diagnosis of high grade and clinically relevant prostate cancer in men with a previous negative biopsy: results from the REDUCE study.

PURPOSE: We assessed whether dutasteride enhances the usefulness of total prostate specific antigen for diagnosing clinically significant prostate cancer. MATERIALS AND METHODS: The 4-year REDUCE study evaluated the efficacy and safety of 0.5 mg dutasteride daily for prostate cancer risk reduction in men with a prostate specific antigen of 2.5 to 10.0 ng/ml and a negative prostate biopsy. Specificity, sensitivity, and positive and negative predictive values of prostate specific antigen for the diagnosis of prostate cancer were assessed. RESULTS: Final prostate specific antigen before biopsy and change from month 6 to final prostate specific antigen performed better for the diagnosis of Gleason score 7-10 tumors in men who received dutasteride vs placebo as assessed by the area under the ROC curves (0.700 vs 0.650, p = 0.0491; and 0.699 vs 0.593, p = 0.0001, respectively). Increases in prostate specific antigen were associated with a higher likelihood of biopsy detectable, Gleason score 7-10 and clinically significant (modified Epstein criteria) prostate cancer. Percentage decreases in prostate specific antigen from baseline to month 6 in the dutasteride arm did not predict prostate cancer overall or Gleason score 7-10 cancer. CONCLUSIONS: In men with a previously negative prostate biopsy, prostate specific antigen performed better during the 4-year study as a marker of prostate cancer in men who received dutasteride vs placebo. The degree of prostate specific antigen increase after 6 months was a better indicator of clinically significant cancer in the dutasteride arm than in the placebo arm. Conversely, the initial decrease in prostate specific antigen in men taking dutasteride did not predict the likelihood of prostate cancer.

Low serum testosterone levels are poor predictors of sexual dysfunction.

OBJECTIVE: • To identify predictors of sexual dysfunction using baseline data from the reduction by dutasteride of prostate cancer events (REDUCE) study. PATIENTS AND METHODS: • REDUCE was a 4-year randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of once-daily dutasteride 0.5 mg in over 8000 men aged 50-75 years with a prostate-specific antigen (PSA) level of 2.5-10 ng/mL (50-60 years) or 3.0-10 ng/mL (>60 years) and a negative prostate biopsy within 6 months of enrolment. • Baseline values (mean serum testosterone, age, International Prostate Symptom Score [IPSS], total prostate volume [TPV], body mass index [BMI], and presence of diabetes/glucose intolerance) were compared in subjects with and without sexual dysfunction (sexual inactivity, impotence, decreased libido or a Problem Assessment Scale of the Sexual Function Index [PAS-SFI] score <9). RESULTS: • Multivariate logistic regression showed that baseline age and IPSS were significant predictors of all four sexual function criteria examined (P < 0.0001). • BMI was a significant predictor of decreased libido, impotence and a PAS-SFI score <9, while diabetes/glucose intolerance was a significant predictor of sexual inactivity, impotence and a PAS-SFI score <9. • Testosterone and TPV were not significant predictors of any sexual function criterion examined. CONCLUSIONS: • Age, IPSS, BMI and diabetes/glucose intolerance, but not serum testosterone or TPV, were significant independent predictors of sexual dysfunction in the REDUCE study population. • The lack of association between sexual dysfunction and serum testosterone questions the value of modestly reduced or low normal testosterone levels as criteria for choosing testosterone replacement in older men with sexual dysfunction.

Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS).

OBJECTIVE: • To assess the efficacy and safety of dutasteride compared with finasteride in treating men with symptomatic benign prostatic hyperplasia (BPH) for 12 months. PATIENTS AND METHODS: • The Enlarged Prostate International Comparator Study was a multicentre, randomized, double-blind, 12-month, parallel-group study. • Men aged ≥ 50 years with a clinical diagnosis of BPH received once-daily treatment with dutasteride 0.5 mg (n= 813) or finasteride 5 mg (n= 817). After a 4-week placebo run-in period, patients were randomized to receive dutasteride or finasteride for 48 weeks, followed by an optional 24-month, open-label phase, during which patients received dutasteride 0.5 mg once daily. • The primary endpoint was change in prostate volume, and the secondary endpoints included improvement in American Urological Association Symptom Index (AUA-SI) scores, improvement in maximum urinary flow rate (Q(max)) and long-term safety in the 24-month open-label phase. RESULTS: • Both dutasteride and finasteride were effective at reducing prostate volume with no significant difference between the two treatments during the study. • Similar reductions in mean AUA-SI scores and Q(max) were also observed for men in both treatment groups. • A similar percentage of adverse events was experienced by patients of both treatment groups, and no new adverse events were reported in the open-label phase. CONCLUSION: • Dutasteride and finasteride, when administered for 12 months, were similarly effective in reducing prostate volume and improving Q(max) and urinary symptoms associated with BPH in men with an enlarged prostate.

Chemoprevention of prostate cancer.

Over the past two decades, many more men are diagnosed with prostate cancer then die of the disease. This increase in diagnosis has led to aggressive treatment of indolent disease in many individuals and has been the impetus for finding a means of reducing the risk of prostate cancer. In the past decade, there have been eight large trials of prostate cancer risk reduction using dietary supplements, 5α-reductase inhibitors, or anti-estrogens. The only two trials which have demonstrated efficacy are those involving 5α-reductase inhibitors: the PCPT (finasteride) and REDUCE (dutasteride). This review examines prostate cancer risk reduction, with emphasis on conclusions that can be drawn from these two landmark studies.

Effects of the oral testosterone undecanoate Kyzatrex™ on ambulatory blood pressure in hypogonadal men.

Testosterone replacement therapies have been shown to increase blood pressure (BP) in hypogonadal men. We studied the effects of a new formulation of testosterone undecanoate (Kyzatrex™) on ambulatory blood pressure (ABP) and heart rate, in 155 men with hypogonadism (mean age, 50.5 years, 76.8% white, 36.1% on antihypertensive therapy). The ABP, heart rate and clinical assessments were obtained at baseline and following 120 and 180 days of therapy. Mean changes from baseline in 24-h ambulatory systolic BP of 1.7 mmHg (95% CI, 0.3, 3.1) at day 120 and 1.8 mmHg (95% CI, 0.3, 3.2) at day 180 were observed post-treatment. For those men on antihypertensive drug therapy, increases in mean 24-h systolic BP were greater than those not taking antihypertensive drugs (3.4 vs 0.7 mmHg at day 120 and 3.1 vs 1.0 mmHg at day 180, respectively). Changes from baseline in 24-h diastolic BP and heart rate at day 120 were smaller (<1 mmHg and <1 beat/min, respectively). There were no relationships observed between testosterone concentration or hemoglobin levels with ABP. Multivariable analyses showed that baseline ambulatory BP and antihypertensive therapy were significantly correlated with BP changes. These data demonstrate small increases in ambulatory BP following 120 days on this oral testosterone undecanoate with no further changes at 180 days. Changes in ambulatory BP were minimal in patients not taking antihypertensive therapy.

PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: validation in the placebo arm of the dutasteride REDUCE trial.

PURPOSE: We determined the performance of PCA3 alone and in the presence of other covariates as an indicator of contemporaneous and future prostate biopsy results in a population with previous negative biopsy and increased serum prostate specific antigen. MATERIALS AND METHODS: Urine PCA3 scores were determined before year 2 and year 4 biopsies from patients in the placebo arm of the REDUCE trial, a prostate cancer risk reduction study evaluating men with moderately increased serum prostate specific antigen results and negative biopsy at baseline. PCA3, serum prostate specific antigen and percent free prostate specific antigen results were correlated with biopsy outcome via univariate logistic regression and ROC analyses. Multivariate logistic regression was also performed including these biomarkers together with prostate volume, age and family history. RESULTS: PCA3 scores were measurable from 1,072 of 1,140 subjects (94% informative rate). PCA3 scores were associated with positive biopsy rate (p <0.0001) and correlated with biopsy Gleason score (p = 0.0017). PCA3 AUC of 0.693 was greater than serum prostate specific antigen (0.612, p = 0.0077 vs PCA3). The multivariate logistic regression model yielded an AUC of 0.753 and exclusion of PCA3 from the model decreased AUC to 0.717 (p = 0.0009). PCA3 at year 2 was a significant predictor of year 4 biopsy outcome (AUC 0.634, p = 0.0002), whereas serum prostate specific antigen and free prostate specific antigen were not predictive (p = 0.3281 and 0.6782, respectively). CONCLUSIONS: PCA3 clinical performance was validated in the largest repeat biopsy study to date. Increased PCA3 scores indicated increased risk of contemporaneous cancers and predicted future biopsy outcomes. Use of PCA3 in combination with serum prostate specific antigen and other risk factors significantly increased diagnostic accuracy.

Overexpression of 5 alpha-reductase type 1 increases sensitivity of prostate cancer cells to low concentrations of testosterone.

INTRODUCTION: Conversion of testosterone to dihydrotestosterone (DHT) by the enzymes 5 alpha-reductase types 1 (5 alpha R1) and 2 (5 alpha R2) is important for normal and pathological growth of the prostate. The predominant isoenzyme in normal prostate is 5 alpha R2. However, prostate cancer (PCa) development is accompanied by a decrease in 5 alpha R2 and an increase in 5 alpha R1. The biological significance of increased 5 alpha R1 expression is not fully understood. Therefore, the aim of this study was to determine the effect of overexpression of 5 alpha R1 on growth and prostate-specific antigen (PSA) production in PCa cells. MATERIALS AND METHODS: LNGK-9 PCa cells, transiently transfected with pTRE-5 alpha R1 or pTRE alone, were cultured in the presence or absence of testosterone at varying concentrations. Cell growth and PSA secretion were measured after 4-6 days. Cyclin E1, Ki67, and PSA mRNA levels were evaluated using RT-PCR after 24 hr of treatment. RESULTS: 10 pM testosterone increased growth of pTRE-5 alpha R1 transfectants by 54.1% over cells grown in the absence of testosterone, compared to 25.0% in pTRE transfectants (P < 0.01). Likewise, PSA secretion was increased by 56-fold in pTRE-5 alpha R1 transfectants treated with 10 pM testosterone, compared to 26-fold in pTRE transfectants (P < 0.01). At concentrations of testosterone above 10 pM, the stimulatory effect on growth and PSA secretion was not distinguishable between pTRE-5 alpha R1 and pTRE transfectants. CONCLUSIONS: These results demonstrate that upregulation of 5 alpha R1 enhances the cellular response to low, but not high, concentrations of testosterone. This explains one mechanism by which castration-recurrent PCa can proliferate in the presence of castrate levels of circulating testosterone.

The rationale for inhibiting 5alpha-reductase isoenzymes in the prevention and treatment of prostate cancer.

PURPOSE: Androgens are essential for prostatic growth and development but they also have a significant role in prostate disease pathogenesis. Dihydrotestosterone, the primary prostatic androgen, is transformed from testosterone by types 1 and 2 5alpha-reductase and, thus, a potential therapeutic benefit could be achieved through the inhibition of 5alpha-reductase. MATERIALS AND METHODS: A literature review was performed using PubMed/MEDLINE and congress abstracts to examine evidence supporting the potential of 5alpha-reductase inhibitors in the primary prevention of prostate cancer and in limiting the progression of diagnosed disease. RESULTS: Prostate disease development is associated with increased expression of each 5alpha-reductase isoenzyme with over expression of type 1 of particular importance in prostate cancer development and progression. The 2 5alpha-reductase inhibitors currently clinically available are finasteride, a type 2 5alpha-reductase inhibitor, and dutasteride, a dual 5alpha-reductase inhibitor. Dual inhibition by dutasteride has been shown to translate into a greater degree and consistency of dihydrotestosterone suppression compared with finasteride. The Prostate Cancer Prevention Trial showed that finasteride significantly decreased the 7-year risk of prostate cancer in men with prostate specific antigen 3.0 ng/ml or less, while the ongoing Reduction by Dutasteride of Prostate Cancer Events study is assessing whether dutasteride decreases the risk of biopsy detectable prostate cancer in men with prostate specific antigen 2.5 to 10 ng/ml and a previous negative biopsy. Small-scale studies have demonstrated potential effects of 5alpha-reductase inhibition in prostate cancer treatment that warrant further investigation, while dutasteride use in men undergoing expectant treatment is also being examined. CONCLUSIONS: The inhibition of 5alpha-reductase represents a valid target for prostate cancer risk reduction and treatment strategies. The greater suppression of dihydrotestosterone observed with agents that inhibit each 5alpha-reductase isoenzyme may translate into enhanced outcomes and studies are under way to test this hypothesis.

Levels of 5alpha-reductase type 1 and type 2 are increased in localized high grade compared to low grade prostate cancer.

PURPOSE: In the prostate testosterone is converted to dihydrotestosterone by 5alpha-reductase type 1 and/or 2. Although 5alpha-reductase type 2 is predominant in normal prostates, type 1 is increased in cancer vs benign tissue. It is unclear whether 5alpha-reductase type 1/2 levels correlate with cancer grade. We compared the relative expression of 5alpha-reductase type 1 and 2 in localized high and low grade prostate cancer. MATERIALS AND METHODS: Immunostaining for 5alpha-reductase type 1/2 was evaluated in 64 prostate tissues from untreated men with localized prostate cancer. The percent of tumor area with moderate-high intensity staining was estimated for each Gleason pattern in the tissues. Adjacent benign tissue was evaluated in 26 prostate cancer specimens. RESULTS: Moderate-high staining for 5alpha-reductase type 1 increased from 18.8% +/- 2.9% (mean +/- SEM) in 34 Gleason pattern 3 cancers to 31.0% +/- 4.1% in 30 Gleason pattern 4/5 cancers (p = 0.016). Staining for 5alpha-reductase type 2 increased from 22.9% +/- 3.0% in 34 Gleason pattern 3 cancers to 39.2% +/- 4.1% in 30 Gleason pattern 4/5 cancers (p = 0.002). Compared to benign prostatic hyperplasia tissues staining for 5alpha-reductase type 1 was greater than 3-fold higher and staining for 5alpha-reductase type 2 was significantly lower in benign tissue adjacent to cancer (p = 0.006 and 0.0236, respectively). CONCLUSIONS: Levels of 5alpha-reductase type 1 and 2 are increased in localized high vs low grade prostate cancer. Levels of 5alpha-reductase type 1 are higher in benign tissue adjacent to cancer than in benign prostatic hyperplasia. These results raise the possibility that increased 5alpha-reductase type 1 in localized high grade cancers may contribute to the decreased effectiveness of the 5alpha-reductase type 2 selective inhibitor finasteride against high grade prostate cancer in the Prostate Cancer Prevention Trial.

5alpha-reductase inhibitors in benign prostatic hyperplasia and prostate cancer risk reduction.

Androgens play an essential role in prostatic development and function, but are also involved in prostate disease pathogenesis. The primary prostatic androgen, dihydrotestosterone (DHT), is synthesized from testosterone by 5alpha-reductase types 1 and 2. Inhibition of the 5alpha-reductase isoenzymes therefore has potential therapeutic benefit in prostate disease. The two currently approved 5alpha-reductase inhibitors (5ARIs), finasteride and dutasteride, have demonstrated long-term efficacy and safety in the treatment of benign prostatic hyperplasia. Finasteride, a type-2 5ARI, has also been studied for its ability to reduce the incidence of biopsy-detectable prostate cancer in the Prostate Cancer Prevention Trial. Treatment with dutasteride, a dual 5ARI, has been shown to result in a greater degree and consistency of DHT suppression compared with finasteride. Two large-scale studies of dutasteride are currently investigating the role of near-maximal DHT suppression in the settings of prostate cancer risk reduction and expectant management of localized prostate cancer.

Delay in the progression of low-risk prostate cancer: rationale and design of the Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial.

PURPOSE: Men with prostate cancer may live as long as men their age without prostate cancer. Those with low-risk disease may benefit from expectant management, which actively monitors disease progression. Dutasteride, a dual 5alpha-reductase inhibitor (5ARI), may delay prostate cancer progression or extend the time to initiation of more aggressive therapy. MATERIALS AND METHODS: The Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial will evaluate whether dutasteride decreases time to prostate cancer progression. Three hundred candidates for expectant management with biopsy-proven, low-risk, localized prostate cancer will receive dutasteride 0.5 mg/day or placebo for 3 years. Eligible men are between 50 and 80 years of age, have clinical stage T1c-T2a prostate cancer, a Gleason score of less than or equal to 6, and serum prostate-specific antigen (PSA) less than or equal to 10 ng/mL. Entry biopsy of at least 10 cores had to be performed within 6 months of screening and will be repeated at 1.5 and 3 years. Men will complete questionnaires to measure symptoms, quality of life (QOL), and anxiety. Because PSA is an important monitoring tool in expectant management that may impact patients' comfort levels, actual PSA values will be provided to physicians and subjects. Time-to-disease progression (primary therapy for prostate cancer or pathologic progression), positive cores, change in Gleason score, and QOL assessments will be compared between groups. RESULTS: The trial completed recruitment of 302 subjects in March 2007. The study will be completed in 2010. CONCLUSIONS: The REDEEM study will evaluate the potential for dutasteride to delay disease progression in men with low-risk, localized prostate cancer. This study will better define which patients with prostate cancer can be managed with less invasive and potentially less debilitating therapy.

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.

The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride.

BACKGROUND: Male pattern hair loss (MPHL) is a potentially reversible condition in which dihydrotestosterone is an important etiologic factor. OBJECTIVE: Our aim was to evaluate the efficacy of the type 1 and 2 5alpha-reductase inhibitor dutasteride in men with MPHL. METHODS: Four hundred sixteen men, 21 to 45 years old, were randomized to receive dutasteride 0.05, 0.1, 0.5 or 2.5 mg, finasteride 5 mg, or placebo daily for 24 weeks. RESULTS: Dutasteride increased target area hair count versus placebo in a dose-dependent fashion and dutasteride 2.5 mg was superior to finasteride at 12 and 24 weeks. Expert panel photographic review and investigator assessment of hair growth confirmed these results. Scalp and serum dihydrotestosterone levels decreased, and testosterone levels increased, in a dose-dependent fashion with dutasteride. LIMITATIONS: The study was limited to 24 weeks. CONCLUSION: Dutasteride increases scalp hair growth in men with MPHL. Type 1 and type 2 5alpha-reductase may be important in the pathogenesis and treatment of MPHL.